Methods of Treating Multiple Sclerosis

ABSTRACT

Provided herein are methods of treating multiple sclerosis with a fumarate, wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a combination of any of the foregoing. The methods provided herein improve the safety of treatment by informing and monitoring patients undergoing treatment regarding progressive multifocal leukoencephalopathy, and/or by monitoring lymphocyte count.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 62/080,783, filed Nov. 17, 2014, U.S. Provisional PatentApplication No. 62/140,255, filed Mar. 30, 2015, and U.S. ProvisionalPatent Application No. 62/232,963, filed Sep. 25, 2015, each of which isincorporated herein by reference in its entirety.

1. FIELD

Provided herein are methods of treating multiple sclerosis with afumarate, such as a dialkyl fumarate, monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, and apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing. The methods provided herein improve the safety of treatmentby informing and monitoring patients undergoing treatment regardingprogressive multifocal leukoencephalopathy (PML), and/or by monitoringlymphocyte count.

2. BACKGROUND

Multiple sclerosis (MS) is an autoimmune disease with the autoimmuneactivity directed against central nervous system (CNS) antigens. Thedisease is characterized by inflammation in parts of the CNS, leading tothe loss of the myelin sheathing around neuronal axons (demyelination),axonal loss, and the eventual death of neurons, oligodendrocytes andglial cells. For a comprehensive review of MS and current therapies,see, e.g., McAlpine's Multiple Sclerosis, by Alastair Compston et al.,4th edition, Churchill Livingstone Elsevier, 2006.

An estimated 2,500,000 people in the world suffer from MS. It is one ofthe most common diseases of the CNS in young adults. MS is a chronic,progressing, disabling disease, which generally strikes its victims sometime after adolescence, with diagnosis generally made between 20 and 40years of age, although onset may occur earlier. The disease is notdirectly hereditary, although genetic susceptibility plays a part in itsdevelopment. MS is a complex disease with heterogeneous clinical,pathological and immunological phenotype.

There are four major clinical types of MS: 1) relapsing-remitting MS(RR-MS), characterized by clearly defined relapses with full recovery orwith sequelae and residual deficit upon recovery; periods betweendisease relapses characterized by a lack of disease progression; 2)secondary progressive MS (SP-MS), characterized by initial relapsingremitting course followed by progression with or without occasionalrelapses, minor remissions, and plateaus; 3) primary progressive MS(PP-MS), characterized by disease progression from onset with occasionalplateaus and temporary minor improvements allowed; and 4) progressiverelapsing MS (PR-MS), characterized by progressive disease onset, withclear acute relapses, with or without full recovery; periods betweenrelapses characterized by continuing progression.

Clinically, the illness most often presents as a relapsing-remittingdisease and, to a lesser extent, as steady progression of neurologicaldisability. Relapsing-remitting MS (RR-MS) presents in the form ofrecurrent attacks of focal or multifocal neurologic dysfunction. Attacksmay occur, remit, and recur, seemingly randomly over many years.Remission is often incomplete and as one attack follows another, astepwise downward progression ensues with increasing permanentneurological deficit. The usual course of RR-MS is characterized byrepeated relapses associated, for the majority of patients, with theeventual onset of disease progression. The subsequent course of thedisease is unpredictable, although most patients with arelapsing-remitting disease will eventually develop secondaryprogressive disease. In the relapsing-remitting phase, relapsesalternate with periods of clinical inactivity and may or may not bemarked by sequelae depending on the presence of neurological deficitsbetween episodes. Periods between relapses during therelapsing-remitting phase are clinically stable. On the other hand,patients with progressive MS exhibit a steady increase in deficits, asdefined above and either from onset or after a period of episodes, butthis designation does not preclude the further occurrence of newrelapses.

MS pathology is, in part, reflected by the formation of focalinflammatory demyelinating lesions in the white matter, which are thehallmarks in patients with acute and relapsing disease. In patients withprogressive disease, the brain is affected in a more global sense, withdiffuse but widespread (mainly axonal) damage in the normal appearingwhite matter and massive demyelination also in the grey matter,particularly, in the cortex.

Salts of fumaric acid esters, in combination with dimethyl fumarate(DMF), such as present in FUMADERM®, have been proposed for thetreatment of MS (see, e.g., Schimrigk et al., Eur. J. Neurol., 2006,13(6):604-610; Drugs R&D, 2005, 6(4):229-30; U.S. Pat. No. 6,436,992).FUMADERM® contains dimethyl fumarate, calcium salt of ethyl hydrogenfumarate, magnesium salt of ethyl hydrogen fumarate, and zinc salt ofethyl hydrogen fumarate (see, e.g., Schimrigk et al., Eur. J. Neurol.,2006, 13(6):604-610).

TECFIDERA®, dimethyl fumarate delayed-release capsules for oral use, wasapproved in 2013 by the U.S. Food and Drug Administration for thetreatment of subjects with relapsing forms of multiple sclerosis.TECFIDERA® contains dimethyl fumarate (DMF), which has the followingstructure:

The first Phase 3 study, DEFINE (ClinicalTrials.gov identifierNCT00420212), demonstrated that DMF significantly reduced clinicalrelapses, accumulation of disability progression, and lesion number andvolume compared with placebo after two years of treatment. See, e.g.,Gold et al., N. Engl. J. Med., 2012, 367(12):1098-1107. These findingswere supported by the results of the second phase 3 study, CONFIRM(ClinicalTrials.gov identifier NCT00451451), which additionallyevaluated subcutaneous glatiramer acetate as an active referencetreatment (rater-blind). See, e.g., Fox et al., N. Engl. J. Med., 2012,367(12):1087- 1097. DMF has demonstrated an acceptable safety profile inthe DEFINE and CONFIRM studies.

There have been case reports of patients with psoriasis, treated withFUMADERM® or compounded fumaric acid esters, who developed PML (Ermis etal., N. Engl. J. Med., 2013, 368(17):1657-1658; van Oosten et al., N.Engl. J. Med., 2013, 368(17):1658-1659; Sweetser et al., N. Engl. J.Med., 2013, 368(17):1659-1658; Emrich, Lisa, “Tecfidera and PML—What'sthe story.” Multiplesclerosis.net, Apr. 25, 2013; accessed Nov. 10,2014).

PML is an opportunistic viral infection caused by a type of polymaviruscalled the JC virus (JCV) that typically only occurs in patients who areimmunocompromised, and that usually leads to death or severe disability.The virus is very common in the general population, occurs in childhood,and persists for life. JCV seroprevalence of ˜33-84% has beendemonstrated, depending on the studies (see WO 2011/085369 A1,WO2007/100770 A2, and WO 2012/166971 A2). PML is a severe and rapidlyprogressive viral disease of the central nervous system that destroysthe myelin coating, which protects the nerve cells. PML occurs almostexclusively in patients who are severely immunocompromised, and is oftenassociated with lymphoproliferative and other chronic diseases, such asAIDS, Hodgkin's disease, chronic lymphocytic leukemia, sarcoidosis,tuberculosis, systemic lupus erythematosus, and organ transplantation.Cases of PML have also been reported in patients with autoimmunedisorders who received immunosuppressive therapy; among these, threepatients with rheumatoid arthritis (Sponzilli et al., Neurology, 1975,25(7):664-668; Rankin et al., J. Rheumatol., 1995, 22(4):777-779; Durezet al., Arthritis Rheum., 2002, 46(98):536), one of whom was treatedwith tumor necrosis factor (TNF) antagonist (Durez et al., ArthritisRheum., 2002, 46(98):536). PML also was reported in a Crohn's Diseasepatient, but the concomitant treatments were not specified (Garrels etal., Am. J. Neuroradiol., 1996, 17(3):597-600), and in patients treatedwith natalizumab, a humanized monoclonal antibody used in the treatmentof multiple sclerosis, and Crohn's disease. In 2005, the first cases ofPML associated with biological immunomodulatory therapy were reported,initially with natalizumab and subsequently in association with otheragents including efalizumab, rituximab, and alemtuzumab (reviewed in:Major et al., Annu. Rev. Med., 2010, 61:35-47).

There is need in the art for safer methods of treating patients withfumarates that take into account the possibility of contracting PML.

3. SUMMARY

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a fumarate to the patient,wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, acombination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug ofmonoalkyl fumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; and (b) monitoring the patient for a sign or symptomsuggestive of progressive multifocal leukoencephalopathy (PML) in thepatient.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising monitoring a patient withmultiple sclerosis who is being treated with a fumarate for a sign orsymptom suggestive of PML in the patient, wherein the fumarate is adialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a pharmaceuticallyacceptable salt, clathrate, solvate, tautomer, or stereoisomer of any ofthe foregoing, or a combination of any of the foregoing.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a fumarate to the patient,wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, acombination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug ofmonoalkyl fumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; and (b) informing the patient that PML has occurred in apatient who received dimethyl fumarate.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a fumarate to the patient,wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, acombination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug ofmonoalkyl fumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; and (b) instructing the patient of the importance ofcontacting the patient's doctor if the patient develops any symptomssuggestive of PML.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising informing a patient withmultiple sclerosis who is being treated with a fumarate that PML hasoccurred in a patient who received dimethyl fumarate, wherein thefumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of adialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising instructing a patient withmultiple sclerosis who is being treated with a fumarate of theimportance of contacting the patient's doctor if the patient developsany symptoms suggestive of PML, wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing.

In one embodiment, the method further comprises withholding treatmentwith the fumarate from the patient at the first sign or symptomsuggestive of PML in the patient.

In one embodiment, the method further comprises performing a diagnosticevaluation for PML in the patient at the first sign or symptomsuggestive of PML in the patient.

In one embodiment, the method further comprises administering atherapeutic to the patient for the treatment for the treatment of PMLwhen the diagnostic evaluation indicates PML in the patient.

In one embodiment, the method further comprises instructing the patientto continue to look for new signs and symptoms suggestive of PML forapproximately 6 months following discontinuation of treatment with thefumarate.

In one embodiment, the method further comprises instructing the patientthat typical symptoms associated with PML are diverse, progress overdays to weeks, and include progressive weakness on one side of the bodyor clumsiness of limbs, disturbance of vision, and changes in thinking,memory, and orientation leading to confusion and personality changes.

In one embodiment, the method further comprises instructing the patientthat progression of deficits associated with PML usually leads to deathor severe disability over weeks or months.

In one embodiment, the diagnostic evaluation comprises a test for thepresence of JC viral DNA in the cerebrospinal fluid of the patient.

In one embodiment, the sign or symptom suggestive of PML is selectedfrom the group consisting of progressive weakness on one side of thebody or clumsiness of limbs, disturbance of vision, and changes inthinking, memory, and orientation leading to confusion and personalitychanges.

In one embodiment, administering is done orally.

In one embodiment, the pharmaceutical composition comprises atherapeutically effective amount of the fumarate and a pharmaceuticallyacceptable carrier.

In one embodiment, the pharmaceutical composition is in the form of atablet or a capsule.

In one embodiment, the pharmaceutical composition is in the form of anenterically coated tablet.

In one embodiment, the pharmaceutical composition is in the form of acapsule containing enterically coated microtablets.

In one embodiment, the fumarate is dimethyl fumarate and/or monomethylfumarate.

In one embodiment, the fumarate is dimethyl fumarate

In one embodiment, the administering is of 240 mg twice daily ofdimethyl fumarate.

In one embodiment, the administering is of 120 mg dimethyl fumaratetwice daily for 7 days, followed by 240 mg dimethyl fumarate twice dailyas a maintenance dose.

In one embodiment, the administering is of not greater than 720 mg dailytotal fumarates.

In one embodiment, the administering is of not greater than 480 mg dailytotal fumarates.

In one embodiment, the pharmaceutical composition consists essentiallyof dimethyl fumarate, and the administering is of not greater than 720mg daily dimethyl fumarate.

In one embodiment, the pharmaceutical composition consists essentiallyof dimethyl fumarate, and the administering is of not greater than 480mg daily dimethyl fumarate.

In one embodiment, the pharmaceutical composition consists essentiallyof dimethyl fumarate.

In one embodiment, the multiple sclerosis is a relapsing form ofmultiple sclerosis.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that a fumarate salt is not present in thepharmaceutical composition; and (b) monitoring the patient for a sign orsymptom suggestive of PML in the patient.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising monitoring a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate for a sign or symptom suggestive ofPML in the patient; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a clathrate, solvate, tautomer, or stereoisomer of anyof the foregoing, or a combination of any of the foregoing; with theproviso that a fumarate salt is not present in the pharmaceuticalcomposition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that a fumarate salt is not present in thepharmaceutical composition; and (b) informing the patient that PML hasoccurred in a patient who received dimethyl fumarate.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that a fumarate salt is not present in thepharmaceutical composition; and (b) instructing the patient of theimportance of contacting the patient's doctor if the patient developsany symptoms suggestive of PML.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising informing a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate that PML has occurred in a patient whoreceived dimethyl fumarate; wherein the fumarate is a dialkyl fumarate,a monoalkyl fumarate, a combination of a dialkyl fumarate and amonoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that a fumarate salt is not present in thepharmaceutical composition.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising instructing a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate of the importance of contacting thepatient's doctor if the patient develops any symptoms suggestive of PML;wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, acombination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug ofmonoalkyl fumarate, a deuterated form of any of the foregoing, or aclathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that afumarate salt is not present in the pharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that an ethylhydrogen fumarate salt is not present in the pharmaceutical composition;and (b) monitoring the patient for a sign or symptom suggestive of PMLin the patient.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising monitoring a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate for a sign or symptom suggestive ofPML in the patient; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a pharmaceutically acceptable salt, clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing; with the proviso that an ethylhydrogen fumarate salt is not present in the pharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that an ethylhydrogen fumarate salt is not present in the pharmaceutical composition;and (b) informing the patient that PML has occurred in a patient whoreceived dimethyl fumarate.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that an ethylhydrogen fumarate salt is not present in the pharmaceutical composition;and (b) instructing the patient of the importance of contacting thepatient's doctor if the patient develops any symptoms suggestive of PML.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising informing a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate that PML has occurred in a patient whoreceived dimethyl fumarate; wherein the fumarate is a dialkyl fumarate,a monoalkyl fumarate, a combination of a dialkyl fumarate and amonoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that an ethylhydrogen fumarate salt is not present in the pharmaceutical composition.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising instructing a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate of the importance of contacting thepatient's doctor if the patient develops any symptoms suggestive of PML;wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, acombination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug ofmonoalkyl fumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that an ethyl hydrogen fumarate salt is notpresent in the pharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition; and (b)monitoring the patient for a sign or symptom suggestive of PML in thepatient.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising monitoring a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate for a sign or symptom suggestive ofPML in the patient; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a pharmaceutically acceptable salt, clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition; and (b)informing the patient that PML has occurred in a patient who receiveddimethyl fumarate.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition; and (b)instructing the patient of the importance of contacting the patient'sdoctor if the patient develops any symptoms suggestive of PML.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising informing a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate that PML has occurred in a patient whoreceived dimethyl fumarate; wherein the fumarate is a dialkyl fumarate,a monoalkyl fumarate, a combination of a dialkyl fumarate and amonoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising instructing a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate of the importance of contacting thepatient's doctor if the patient develops any symptoms suggestive of PML;wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, acombination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug ofmonoalkyl fumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that ethyl hydrogen fumarate calcium salt,ethyl hydrogen fumarate magnesium salt, ethyl hydrogen fumarate zincsalt, and ethyl hydrogen fumarate copper salt are not present in thepharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositionconsisting essentially of dimethyl fumarate and/or monomethyl fumarateto the patient; and (b) monitoring the patient for a sign or symptomsuggestive of PML in the patient.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising monitoring a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition consisting essentially of dimethyl fumarate and/ormonomethyl fumarate for a sign or symptom suggestive of PML in thepatient.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositionconsisting essentially of dimethyl fumarate and/or monomethyl fumarateto the patient; and (b) informing the patient that PML has occurred in apatient who received dimethyl fumarate.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositionconsisting essentially of dimethyl fumarate and/or monomethyl fumarateto the patient; and (b) instructing the patient of the importance ofcontacting the patient's doctor if the patient develops any symptomssuggestive of PML.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising informing a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition consisting essentially of dimethyl fumarate and/ormonomethyl fumarate that PML has occurred in a patient who receiveddimethyl fumarate.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising instructing a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition consisting essentially of dimethyl fumarate and/ormonomethyl fumarate of the importance of contacting the patient's doctorif the patient develops any symptoms suggestive of PML.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a fumarate to the patient,wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, acombination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug ofmonoalkyl fumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; and (b) obtaining a complete blood count including lymphocytecount after 6 months of repeated administering of said pharmaceuticalcomposition to said patient, and every 6 to 12 months thereafter.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that a fumarate salt is not present in thepharmaceutical composition; and (b) obtaining a complete blood countincluding lymphocyte count after 6 months of repeated administering ofsaid pharmaceutical composition to said patient, and every 6 to 12months thereafter.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that an ethylhydrogen fumarate salt is not present in the pharmaceutical composition;and (b) obtaining a complete blood count including lymphocyte countafter 6 months of repeated administering of said pharmaceuticalcomposition to said patient, and every 6 to 12 months thereafter.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition; and (b)obtaining a complete blood count including lymphocyte count after 6months of repeated administering of said pharmaceutical composition tosaid patient, and every 6 to 12 months thereafter.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositionconsisting essentially of dimethyl fumarate and/or monomethyl fumarateto the patient; and (b) obtaining a complete blood count includinglymphocyte count after 6 months of repeated administering of saidpharmaceutical composition to said patient, and every 6 to 12 monthsthereafter.

In one embodiment, the method further comprises interruptingadministering of said pharmaceutical composition to said patient whenthe patient has a lymphocyte count less than 0.5 x 10⁹/L persisting formore than six months.

In one embodiment, the method further comprises measuring lymphocytecount in said patient until lymphopenia is resolved in said patient.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) prior to initiating treatment of the patientwith a pharmaceutical composition comprising a fumarate: (i) performinga complete blood count including lymphocyte count; and (ii) if thelymphocyte count is found to be below the normal range, consideringalternative causes of lymphopenia, and taking corrective measures asappropriate regarding said alternative causes; and (b) administeringsaid pharmaceutical composition to the patient, wherein the fumarate isa dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a pharmaceuticallyacceptable salt, clathrate, solvate, tautomer, or stereoisomer of any ofthe foregoing, or a combination of any of the foregoing.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) repeatedly administering a pharmaceuticalcomposition comprising a fumarate to the patient; wherein the fumarateis a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a pharmaceuticallyacceptable salt, clathrate, solvate, tautomer, or stereoisomer of any ofthe foregoing, or a combination of any of the foregoing; and (b)obtaining a complete blood count including lymphocyte count every 3months after starting therapy of said patient with said pharmaceuticalcomposition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; and (b) monitoring the patientclosely for signs or symptoms of appearance of new neurologicaldysfunction if the patient experiences lymphopenia after administeringof said pharmaceutical composition.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising monitoring a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate, and who experiences lymphopenia, forsigns or symptoms of appearance of new neurological dysfunction; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing.

Provided herein is a method of treating multiple sclerosis in a patientwho is being treated with a multiple sclerosis disease-modifying therapyother than a pharmaceutical composition comprising a fumarate; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; said method comprising the following steps in the statedorder: (a) stopping administration of said multiple sclerosisdisease-modifying therapy to said patient; (b) considering the half-lifeand mode of action of said multiple sclerosis disease-modifying therapyin order to avoid an additive immune effect whilst at the same timeminimizing the risk of disease reactivation; and (c) administering thepharmaceutical composition comprising the fumarate to the patient.

Provided herein is a method of treating multiple sclerosis in a patientwho is being treated with interferon or glatiramer acetate, said methodcomprising (a) discontinuing administration of interferon or glatirameracetate to the patient; and (b) immediately after said discontinuing,starting administering to the patient of a pharmaceutical compositioncomprising a fumarate; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a pharmaceutically acceptable salt, clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; and (b) prior to the initialadministering of the pharmaceutical composition comprising the fumarateto the patient, and periodically during treatment of said patient withsaid pharmaceutical composition comprising the fumarate, having a bloodtest done to count the number of white blood cells in the patient; and(c) considering stopping said treatment with said pharmaceuticalcomposition comprising the fumarate if the number of white blood cellsdecreases during said treatment.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) prior to initiating treatment of the patientwith a pharmaceutical composition comprising a fumarate: (i) performinga complete blood count including lymphocyte count; and (ii) if thelymphocyte count is found to be below the normal range, consideringalternative causes of lymphopenia, and taking corrective measures asappropriate regarding said alternative causes; and (b) administeringsaid pharmaceutical composition to the patient, wherein the fumarate isa dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a clathrate, solvate,tautomer, or stereoisomer of any of the foregoing, or a combination ofany of the foregoing; with the proviso that a fumarate salt is notpresent in the pharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) repeatedly administering a pharmaceuticalcomposition comprising a fumarate to the patient; wherein the fumarateis a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a clathrate, solvate,tautomer, or stereoisomer of any of the foregoing, or a combination ofany of the foregoing; with the proviso that a fumarate salt is notpresent in the pharmaceutical composition; and (b) obtaining a completeblood count including lymphocyte count every 3 months after startingtherapy of said patient with said pharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that a fumarate salt is not present in thepharmaceutical composition; and (b) monitoring the patient closely forsigns or symptoms of appearance of new neurological dysfunction if thepatient experiences lymphopenia after administering of saidpharmaceutical composition.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising monitoring a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate, and who experiences lymphopenia, forsigns or symptoms of appearance of new neurological dysfunction; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or a clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing; with the proviso that a fumaratesalt is not present in the pharmaceutical composition.

Provided herein is a method of treating multiple sclerosis in a patientwho is being treated with a multiple sclerosis disease-modifying therapyother than a pharmaceutical composition comprising a fumarate; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or a clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing; with the proviso that a fumaratesalt is not present in the pharmaceutical composition; said methodcomprising the following steps in the stated order: (a) stoppingadministration of said multiple sclerosis disease-modifying therapy tosaid patient; (b) considering the half-life and mode of action of saidmultiple sclerosis disease-modifying therapy in order to avoid anadditive immune effect whilst at the same time minimizing the risk ofdisease reactivation; and (c) administering the pharmaceuticalcomposition comprising the fumarate to the patient.

Provided herein is a method of treating multiple sclerosis in a patientwho is being treated with interferon or glatiramer acetate, said methodcomprising (a) discontinuing administration of interferon or glatirameracetate to the patient; and (b) immediately after said discontinuing,starting administering to the patient of a pharmaceutical compositioncomprising a fumarate; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a clathrate, solvate, tautomer, or stereoisomer of anyof the foregoing, or a combination of any of the foregoing; with theproviso that a fumarate salt is not present in the pharmaceuticalcomposition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that a fumarate salt is not present in thepharmaceutical composition; and (b) prior to the initial administeringof the pharmaceutical composition comprising the fumarate to thepatient, and periodically during treatment of said patient with saidpharmaceutical composition comprising the fumarate, having a blood testdone to count the number of white blood cells in the patient; and (c)considering stopping said treatment with said pharmaceutical compositioncomprising the fumarate if the number of white blood cells decreasesduring said treatment.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) prior to initiating treatment of the patientwith a pharmaceutical composition comprising a fumarate: (i) performinga complete blood count including lymphocyte count; and (ii) if thelymphocyte count is found to be below the normal range, consideringalternative causes of lymphopenia, and taking corrective measures asappropriate regarding said alternative causes; and (b) administeringsaid pharmaceutical composition to the patient, wherein the fumarate isa dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a pharmaceuticallyacceptable salt, clathrate, solvate, tautomer, or stereoisomer of any ofthe foregoing, or a combination of any of the foregoing; with theproviso that an ethyl hydrogen fumarate salt is not present in thepharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) repeatedly administering a pharmaceuticalcomposition comprising a fumarate to the patient; wherein the fumarateis a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a pharmaceuticallyacceptable salt, clathrate, solvate, tautomer, or stereoisomer of any ofthe foregoing, or a combination of any of the foregoing; with theproviso that an ethyl hydrogen fumarate salt is not present in thepharmaceutical composition; and (b) obtaining a complete blood countincluding lymphocyte count every 3 months after starting therapy of saidpatient with said pharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that an ethylhydrogen fumarate salt is not present in the pharmaceutical composition;and (b) monitoring the patient closely for signs or symptoms ofappearance of new neurological dysfunction if the patient experienceslymphopenia after administering of said pharmaceutical composition.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising monitoring a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate, and who experiences lymphopenia, forsigns or symptoms of appearance of new neurological dysfunction; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that an ethyl hydrogen fumarate salt is notpresent in the pharmaceutical composition.

Provided herein is a method of treating multiple sclerosis in a patientwho is being treated with a multiple sclerosis disease-modifying therapyother than a pharmaceutical composition comprising a fumarate; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that an ethyl hydrogen fumarate salt is notpresent in the pharmaceutical composition; said method comprising thefollowing steps in the stated order: (a) stopping administration of saidmultiple sclerosis disease-modifying therapy to said patient; (b)considering the half-life and mode of action of said multiple sclerosisdisease-modifying therapy in order to avoid an additive immune effectwhilst at the same time minimizing the risk of disease reactivation; and(c) administering the pharmaceutical composition comprising the fumarateto the patient.

Provided herein is a method of treating multiple sclerosis in a patientwho is being treated with interferon or glatiramer acetate, said methodcomprising (a) discontinuing administration of interferon or glatirameracetate to the patient; and (b) immediately after said discontinuing,starting administering to the patient of a pharmaceutical compositioncomprising a fumarate; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a pharmaceutically acceptable salt, clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing; with the proviso that an ethylhydrogen fumarate salt is not present in the pharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that an ethylhydrogen fumarate salt is not present in the pharmaceutical composition;and (b) prior to the initial administering of the pharmaceuticalcomposition comprising the fumarate to the patient, and periodicallyduring treatment of said patient with said pharmaceutical compositioncomprising the fumarate, having a blood test done to count the number ofwhite blood cells in the patient; and (c) considering stopping saidtreatment with said pharmaceutical composition comprising the fumarateif the number of white blood cells decreases during said treatment.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) prior to initiating treatment of the patientwith a pharmaceutical composition comprising a fumarate: (i) performinga complete blood count including lymphocyte count; and (ii) if thelymphocyte count is found to be below the normal range, consideringalternative causes of lymphopenia, and taking corrective measures asappropriate regarding said alternative causes; and (b) administeringsaid pharmaceutical composition to the patient, wherein the fumarate isa dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a pharmaceuticallyacceptable salt, clathrate, solvate, tautomer, or stereoisomer of any ofthe foregoing, or a combination of any of the foregoing; with theproviso that ethyl hydrogen fumarate calcium salt, ethyl hydrogenfumarate magnesium salt, ethyl hydrogen fumarate zinc salt, and ethylhydrogen fumarate copper salt are not present in the pharmaceuticalcomposition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) repeatedly administering a pharmaceuticalcomposition comprising a fumarate to the patient; wherein the fumarateis a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a pharmaceuticallyacceptable salt, clathrate, solvate, tautomer, or stereoisomer of any ofthe foregoing, or a combination of any of the foregoing; with theproviso that ethyl hydrogen fumarate calcium salt, ethyl hydrogenfumarate magnesium salt, ethyl hydrogen fumarate zinc salt, and ethylhydrogen fumarate copper salt are not present in the pharmaceuticalcomposition; and (b) obtaining a complete blood count includinglymphocyte count every 3 months after starting therapy of said patientwith said pharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition; and (b)monitoring the patient closely for signs or symptoms of appearance ofnew neurological dysfunction if the patient experiences lymphopeniaafter administering of said pharmaceutical composition.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising monitoring a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate, and who experiences lymphopenia, forsigns or symptoms of appearance of new neurological dysfunction; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that ethyl hydrogen fumarate calcium salt,ethyl hydrogen fumarate magnesium salt, ethyl hydrogen fumarate zincsalt, and ethyl hydrogen fumarate copper salt are not present in thepharmaceutical composition.

Provided herein is a method of treating multiple sclerosis in a patientwho is being treated with a multiple sclerosis disease-modifying therapyother than a pharmaceutical composition comprising a fumarate; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that ethyl hydrogen fumarate calcium salt,ethyl hydrogen fumarate magnesium salt, ethyl hydrogen fumarate zincsalt, and ethyl hydrogen fumarate copper salt are not present in thepharmaceutical composition; said method comprising the following stepsin the stated order: (a) stopping administration of said multiplesclerosis disease-modifying therapy to said patient; (b) considering thehalf-life and mode of action of said multiple sclerosisdisease-modifying therapy in order to avoid an additive immune effectwhilst at the same time minimizing the risk of disease reactivation; and(c) administering the pharmaceutical composition comprising the fumarateto the patient.

Provided herein is a method of treating multiple sclerosis in a patientwho is being treated with interferon or glatiramer acetate, said methodcomprising (a) discontinuing administration of interferon or glatirameracetate to the patient; and (b) immediately after said discontinuing,starting administering to the patient of a pharmaceutical compositioncomprising a fumarate; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a pharmaceutically acceptable salt, clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition; and (b) prior tothe initial administering of the pharmaceutical composition comprisingthe fumarate to the patient, and periodically during treatment of saidpatient with said pharmaceutical composition comprising the fumarate,having a blood test done to count the number of white blood cells in thepatient; and (c) considering stopping said treatment with saidpharmaceutical composition comprising the fumarate if the number ofwhite blood cells decreases during said treatment.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) prior to initiating treatment of the patientwith a pharmaceutical composition consisting essentially of dimethylfumarate and/or monomethyl fumarate: (i) performing a complete bloodcount including lymphocyte count; and (ii) if the lymphocyte count isfound to be below the normal range, considering alternative causes oflymphopenia, and taking corrective measures as appropriate regardingsaid alternative causes; and (b) administering said pharmaceuticalcomposition to the patient.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) repeatedly administering a pharmaceuticalcomposition consisting essentially of dimethyl fumarate and/ormonomethyl fumarate to the patient; and (b) obtaining a complete bloodcount including lymphocyte count every 3 months after starting therapyof said patient with said pharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositionconsisting essentially of dimethyl fumarate and/or monomethyl fumarateto the patient; and (b) monitoring the patient closely for signs orsymptoms of appearance of new neurological dysfunction if the patientexperiences lymphopenia after administering of said pharmaceuticalcomposition.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising monitoring a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition consisting essentially of dimethyl fumarate and/ormonomethyl fumarate, and who experiences lymphopenia, for signs orsymptoms of appearance of new neurological dysfunction.

Provided herein is a method of treating multiple sclerosis in a patientwho is being treated with a multiple sclerosis disease-modifying therapyother than a pharmaceutical composition consisting essentially ofdimethyl fumarate and/or monomethyl fumarate; said method comprising thefollowing steps in the stated order: (a) stopping administration of saidmultiple sclerosis disease-modifying therapy to said patient; (b)considering the half-life and mode of action of said multiple sclerosisdisease-modifying therapy in order to avoid an additive immune effectwhilst at the same time minimizing the risk of disease reactivation; and(c) administering the pharmaceutical composition consisting essentiallyof dimethyl fumarate and/or monomethyl fumarate.

Provided herein is a method of treating multiple sclerosis in a patientwho is being treated with interferon or glatiramer acetate, said methodcomprising (a) discontinuing administration of interferon or glatirameracetate to the patient; and (b) immediately after said discontinuing,starting administering a pharmaceutical composition consistingessentially of dimethyl fumarate and/or monomethyl fumarate to thepatient.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositionconsisting essentially of dimethyl fumarate and/or monomethyl fumarateto the patient; and (b) prior to the initial administering of saidpharmaceutical composition to the patient, and periodically duringtreatment of said patient with said pharmaceutical composition, having ablood test done to count the number of white blood cells in the patient;and (c) considering stopping said treatment with said pharmaceuticalcomposition if the number of white blood cells decreases during saidtreatment.

In one embodiment, the method further comprises discontinuingadministering of said pharmaceutical composition to said patient whenthe patient has a lymphocyte count less than 0.7×10⁹/L that is confirmedon repeat testing after 3 months.

In one embodiment, the signs or symptoms of appearance of newneurological dysfunction comprise motor dysfunction and cognitive orpsychiatric symptoms.

In one embodiment, the method further comprises: if PML is suspected,withholding treatment with said pharmaceutical composition immediatelyand performing further evaluations.

In one embodiment, the method further comprises performing an MRI on thepatient before said starting administering to the patient of thepharmaceutical composition comprising the fumarate.

3.1 Terminology

In order to provide a clear and consistent understanding of thespecification and claims, the following definitions are provided:

The term “alkanediyl,” as used herein refers to linear or branched alkylchains with, for example 1 to 6 carbon atoms. Representative examples ofalkanediyl groups include, but are not limited to —CH₂—, —(CH₂)₂,—CH(CH₃)—, —(CH₂)₃—, —CH₂CH(CH₃)—, —CH(CH₃)CH₂—, —CH(C₂H₅)—, —C(CH₃)₂—,—(CH₂)₄—, —(CH₂)₂CH(CH₃)—, —CH₂CH(CH₃)CH₂—, —CH(CH₃)(CH₂)₂—,—CH(C₂H₅)CH₂—, —CH₂CH(C₂H₅)—, —C(CH₃)₂CH₂—, —CH₂C(CH₃)₂—,—CH(CH₃)CH(CH₃), —CH(C₃H₇)—, —(CH₂)₅, —(CH₂)₃CH(CH₃),—(CH₂)₂CH(CH₃)CH₂—, —CH₂CHCH₃(CH₂)₂—, —CH₂C(CH₃)₂CH₂—, —(CH₂)₂C(CH₃)₂—,—(CH₂)₆—, —(CH₂)₄CH(CH₃)—, —(CH₂)₃CH(CH₃)CH₂—, —CH₂CHCH₃(CH₂)₃—,—(CH₂)₃C(CH₃)₂—, and —(CH₂)₂C(CH₃)₂CH₂—.

The term “alkenyl,” as used herein, refers to a monovalent straight orbranched chain hydrocarbon having from two to six carbons and at leastone carbon-carbon double bond. Representative examples of alkenyl groupsinclude, but are not limited to, —CH=CH₂, —CH═CH—CH₃, —CH₂—CH═CH—CH₃, or—CH(CH₃)—CH═CH—CH₃.

The term “alkyl,” as used herein, refers to a fully saturated branchedor unbranched hydrocarbon moiety. In one embodiment, the alkyl comprises1 to 20 carbon atoms, 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkylgroups include, but are not limited to, methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl,2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, or n-decyl.

The term “alkynyl,” as used herein, refers to a monovalent straight orbranched chain hydrocarbon having from two to six carbons and at leastone carbon-carbon triple bond. Representative examples of alkynyl groupsinclude, but are not limited to, 2-propynyl, 3-butynyl, 2-butynyl,4-pentynyl, 3-pentynyl.

The term “aryl,” as used herein, refers to monocyclic, bicyclic ortricyclic aromatic hydrocarbon groups having, for example, from 5 to 14carbon atoms in the ring portion. In one embodiment, the aryl refers tomonocyclic and bicyclic aromatic hydrocarbon groups having from 6 to 10carbon atoms. Representative examples of aryl groups include, but arenot limited to, phenyl, naphthyl, fluorenyl, and anthracenyl.

The term “arylalkyl,” as used herein, refers to an acyclic alkyl groupin which one of the hydrogen atoms bonded to a carbon atom, typically aterminal or sp³ carbon atom, is replaced with an aryl group.Representative examples of arylalkyl groups include, but are not limitedto, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,naphthobenzyl, or 2-naphthophenylethan-1-yl. In certain embodiments, anarylalkyl group is C₇₋₃₀ arylalkyl, e.g., the alkyl moiety of thearylalkyl group is C₁₋₁₀ and the aryl moiety is C₆₋₂₀. In certainembodiments, an arylalkyl group is C₆₋₁₈ arylalkyl, e.g., the alkylmoiety of the arylalkyl group is C₁₋₈ and the aryl moiety is C₆₋₁₀. Incertain embodiments, the arylalkyl group is C₇₋₁₂ arylalkyl.

The term “alkyl linker,” as used herein, refers to C₁, C₂, C₃, C₄, C₅ orC₆ straight chain (linear) saturated aliphatic hydrocarbon groups andC₃, C₄, C₅ or C₆ branched saturated aliphatic hydrocarbon groups. In oneembodiment, a C₁₋₆ alkyl linker is a C₁, C₂, C₃, C₄, C₅,or C₆ alkyllinker group. Representative examples of alkyl linkers include, but arenot limited to, moieties having from one to six carbon atoms, such as,methyl (—CH₂—), ethyl (—CH₂CH₂—), n-propyl (—CH₂CH₂CH₂—), i-propyl(—CHCH₃CH₂—), n-butyl (—CH₂CH₂CH₂CH₂—), s-butyl (—CHCH₃CH₂CH₂—), i-butyl(—C(CH₃)₂CH₂—), n-pentyl (—CH₂CH₂CH₂CH₂CH₂—), s-pentyl(—CHCH₃CH₂CH₂CH₂—), or n-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₂-). The term“substituted alkyl linker” refers to alkyl linkers having substituentsreplacing one or more hydrogen atoms on one or more carbons of thehydrocarbon backbone. Such substituents do not alter thesp³-hybridization of the carbon atom to which they are attached andinclude those substituents listed below in the definition of the term“substituted.”

The term “carbocycle,” as used herein, refers to any stable monocyclic,bicyclic or tricyclic ring having the specified number of carbons, anyof which may be saturated or unsaturated. In one embodiment, a C₃₋₁₄carbocycle is intended to include a monocyclic, bicyclic, tricyclic, orspirocyclic (mono- or polycyclic) ring having 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, or 14 carbon atoms. Representative examples of carbocyclesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl,cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,fluorenyl, phenyl, naphthyl, indanyl, adamantly, tetrahydronaphthyl,octahydropentalene, ocatahydro-1H-indene, bicyclo[2.2.2]octane,spiro[3.4]octane, spiro[4.5]decane, spiro[4.5]deca-1,6-diene, anddispiro[2.2.4.2]dodecane. In one embodiment, the bridge linking tonon-adjacent carbon atoms to form a tricyclic ring is a C₁ or C₂ bridge.When a ring is bridged, the substituents recited for the ring may alsobe present on the bridge.

The term “cycloalkyl,” as used herein, refers to a saturated orpartially unsaturated cyclic alkyl group. Representative examples ofcycloalkyl groups include, but are not limited to, cyclopropane,cyclobutane, cyclopentane, or cyclohexane. In one embodiment, acycloalkyl group is C₃₋₁₅ cycloalkyl, C₃₋₁₂ cycloalkyl, or C₃₋₈cycloalkyl.

The term “cycloalkylalkyl,” as used herein, refers to an acyclic alkylgroup in which one of the hydrogen atoms bonded to a carbon atom,typically a terminal or sp³ carbon atom, is replaced with a cycloalkylgroup. In certain embodiments, a cycloalkylalkyl group is C₄₋₃₀cycloalkylalkyl, and, for example, the alkyl moiety of thecycloalkylalkyl group is C₁₋₁₀ and the cycloalkyl moiety is C₃₋₂₀. Inanother embodiment, a cycloalkylalkyl group is C₃₋₂₀ cycloalkylalkyl,and, for example, the alkyl moiety of the cycloalkylalkyl group is C₁₋₈and the cycloalkyl moiety is C₃₋₁₂. In a particular embodiment, acycloalkylalkyl group is C₄₋₁₂ cycloalkylalkyl.

The term “deuterium enrichment factor”, as used herein, refers to theratio between the isotopic abundance and the natural abundance ofdeuterium in a given sample of a compound.

The term “deuterium incorporation percentage,” as used herein, refers tothe percentage of the molecules having deuterium at a particularposition in a given sample of a compound out of the total amount of themolecules including deuterated and non-deuterated.

The terms “deuterated methyl” and “deuterated ethyl,” as used herein,refer to a methyl group and ethyl group, respectively, that contains atleast one deuterium atom. Examples of deuterated methyl include —CDH₂,—CD₂H, and —CD₃. Examples of deuterated ethyl include, but are notlimited to, —CHDCH₃, —CD₂CH₃, —CHDCDH₂, —CH₂CD₃.

The term “halogen,” as used herein, refers to fluoro, chloro, bromo, oriodo.

The term “heteroalkyl,” as used herein, by itself or as part of anothersubstituent refers to an alkyl group in which one or more of the carbonatoms (and certain associated hydrogen atoms) are independently replacedwith heteroatomic groups. Examples of heteroatomic groups include, butare not limited to, —O—, —S—, —O—O—, —S—S—, —O—S—, —NR′, ═N—N═, —N═N—,—-N═N—NR′—, —PR′—, —P(O)₂—, —POR′—, —O—P(O)₂—, —SO—, —SO₂—, and—Sn(R′)₂—, where each R′ is independently hydrogen, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₆₋₁₂ aryl, substituted C₆₋₁₂ aryl, C₇₋₁₈arylalkyl, substituted C₇₋₁₈ arylalkyl, C₃₋₇ cycloalkyl, substitutedC₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl, substituted C₃₋₇heterocycloalkyl, C₁₋₆ heteroalkyl, substituted C₁₋₆ heteroalkyl, C₆₋₁₂heteroaryl, substituted C₆₋₁₂ heteroaryl, C₇₋₁₈ heteroarylalkyl, orsubstituted C₇₋₁₈ heteroarylalkyl. In one embodiment, a C₁₋₆heteroalkyl, means, for example, a C₁₋₆ alkyl group in which at leastone of the carbon atoms (and certain associated hydrogen atoms) isreplaced with a heteroatom. In a particular embodiment, a C₁₋₆heteroalkyl, for example, includes groups having five carbon atoms andone heteroatom, groups having four carbon atoms and two heteroatoms,etc. In one embodiment, each R′ is independently hydrogen or C₁₋₃ alkyl.In another embodiment, a heteroatomic group is —O—, —S—, —NH—, —N(CH₃)—,or —SO₂—. In a specific embodiment, the heteroatomic group is —O—.

The term “heteroaryl,” as used herein, refers to, for example, a 5-14membered monocyclic-, bicyclic-, or tricyclic-ring system, having 1 to10 heteroatoms independently selected from N, O, or S, wherein N and Scan be optionally oxidized to various oxidation states, and wherein atleast one ring in the ring system is aromatic. In one embodiment, theheteroaryl is monocyclic and has 5 or 6 ring members. Representativeexamples of monocyclic heteroaryl groups include, but are not limitedto, pyridyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl and tetrazolyl. In another embodiment, the heteroaryl isbicyclic and has from 8 to 10 ring members. Representative examples ofbicyclic heteroaryl groups include indolyl, benzofuranyl, quinolyl,isoquinolyl indazolyl, indolinyl, isoindolyl, indolizinyl,benzamidazolyl, quinolinyl, 5,6,7,8-tetrahydroquinoline, and6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine.

The term “heteroarylalkyl,” as used herein, refers to an acyclic alkylgroup in which one of the hydrogen atoms bonded to a carbon atom,typically a terminal or sp³ carbon atom, is replaced with a heteroarylgroup. In certain embodiments, a heteroarylalkyl group is C₇₋₁₂heteroarylalkyl, and, for example, the alkyl moiety of theheteroarylalkyl group is C₁₋₂ and the heteroaryl moiety is C₆₋₁₀.

The term “heterocycle,” as used herein, refers to any ring structure(saturated or partially unsaturated) which contains at least one ringheteroatom (e.g., N, O or S). Examples of heterocycles include, but arenot limited to, morpholine, pyrrolidine, tetrahydrothiophene,piperidine, piperazine and tetrahydrofuran.

The term “heterocycloalkyl,” as used herein, refers to a saturated orunsaturated cyclic alkyl group in which one or more carbon atoms (andcertain associated hydrogen atoms) are independently replaced with oneor more heteroatoms; or to a parent aromatic ring system in which one ormore carbon atoms (and certain associated hydrogen atoms) areindependently replaced with one or more heteroatoms such that the ringsystem no longer contains at least one aromatic ring. Representativeexamples of heteroatoms to replace the carbon atom(s) include, but arenot limited to, N, P, O, S, and Si. Representative examples ofheterocycloalkyl groups include, but are not limited to, epoxides,azirines, thiuranes, imidazolidine, morpholine, piperazine, piperidine,pyrazolidine, pyrrolidine, and quinuclidine. In one embodiment, aheterocycloalkyl group is C₅₋₁₀ heterocycloalkyl, C₅₋₈ heterocycloalkyl.In a specific embodiment, a heterocycloalkyl group is C₅₋₆heterocycloalkyl.

The term “heterocycloalkylalkyl,” as used herein, refers to an acyclicalkyl group in which one of the hydrogen atoms bonded to a carbon atom,typically a terminal or sp³ carbon atom, is replaced with aheterocycloalkyl group. In certain embodiments, a heterocycloalkylalkylgroup is C₇₋₁₂ heterocycloalkylalkyl, and, for example, the alkyl moietyof the heterocycloalkylalkyl group is C₁₋₂ and the heterocycloalkylmoiety is C₆₋₁₀.

The term “isotopologue,” as used herein, refers to an isotopicallyenriched fumarate.

The term “isotopically enriched,” as used herein, refers to an atomhaving an isotopic composition other than the natural isotopiccomposition of that atom. In one embodiment, an “isotopically enriched”fumarate contains at least one atom having an isotopic composition otherthan the natural isotopic composition of that atom.

The term “isotopic composition,” as used herein, refers to the amount ofeach isotope present for a given atom.

The term “pharmaceutically acceptable salt,” as used herein, refers to asalt prepared from a pharmaceutically acceptable non-toxic acid or baseincluding an inorganic acid and base and an organic acid and base.Suitable pharmaceutically acceptable base addition salts of thefumarates provided herein include, but are not limited to, metallicsalts made from aluminum, calcium, lithium, magnesium, potassium, sodiumand zinc or organic salts made from lysine,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitablenon-toxic acids include, but are not limited to, inorganic and organicacids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic,galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic,phosphoric, propionic, salicylic, stearic, succinic, sulfanilic,sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxicacids include hydrochloric, hydrobromic, phosphoric, sulfuric, andmethanesulfonic acids. Others are well known in the art, see forexample, Remington's Pharmaceutical Sciences, 18th eds., MackPublishing, Easton Pa. (1990) or Remington: The Science and Practice ofPharmacy, 19th eds., Mack Publishing, Easton Pa. (1995).

The term “stereoisomer” as used herein refers to one stereoisomer of afumarate that is substantially free of other stereoisomers of thatfumarate. For example, a “stereomerically pure” fumarate having onechiral center will be substantially free of the opposite enantiomer ofthe fumarate. A “stereomerically pure” fumarate having two chiralcenters will be substantially free of the other diastereomers of thefumarate. A typical “stereomerically pure” fumarate comprises greaterthan about 80% by weight of one stereoisomer of the fumarate and lessthan about 20% by weight of other stereoisomers of the fumarate, greaterthan about 90% by weight of one stereoisomer of the fumarate and lessthan about 10% by weight of the other stereoisomers of the fumarate,greater than about 95% by weight of one stereoisomer of the fumarate andless than about 5% by weight of the other stereoisomers of the fumarate,or greater than about 97% by weight of one stereoisomer of the fumarateand less than about 3% by weight of the other stereoisomers of thefumarate. The fumarate can have chiral centers and can occur asracemates, individual enantiomers or diastereomers, and mixtures thereofAll such isomeric forms are included within the embodiments disclosedherein, including mixtures thereof. The use of stereomerically pureforms of such fumarates, as well as the use of mixtures of those forms,are encompassed by the embodiments disclosed herein. For example,mixtures comprising equal or unequal amounts of the enantiomers of aparticular fumarate may be used in methods and compositions disclosedherein. These isomers may be asymmetrically synthesized or resolvedusing standard techniques such as chiral columns or chiral resolvingagents. See, e.g., Jacques, J., et al., Enantiomers, Racemates andResolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al.,Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of CarbonCompounds (McGraw Hill, N.Y., 1962); and Wilen, S. H., Tables ofResolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind., 1972).

The term “substituted,” as used herein, refers to a group in which oneor more hydrogen atoms are independently replaced with the same ordifferent substituent group(s). In certain embodiments, each substituentgroup is independently halogen, —OH, —CN, —CF₃, ═O, —NO₂, benzyl,—C(O)NH₂, —R″, —OR″, —C(O)R″, —COOR″, —S(O)₂R″or —NR₂″ wherein each R″is independently hydrogen or C₁₋₆ alkyl. In certain embodiments, eachsubstituent group is independently halogen, —OH, —CN, —CF₃, —NO₂,benzyl, —R″, —OR″, or —NR₂″ wherein each R″ is independently hydrogen orC₁₋₄ alkyl. In certain embodiments, each substituent group isindependently halogen, —OH, —CN, —CF₃, ═O, —NO₂, benzyl, —C(O)NR₂″, —R″,—OR″, —C(O)R″, —COOR″, or —NR₂″ wherein each R″ is independentlyhydrogen or C₁₋₄ alkyl. In certain embodiments, each substituent groupis independently —OH, C₁₋₄ alkyl, and —NH₂.

The number of carbon atoms in a group is specified herein by the prefix“C_(x-xx)”, wherein x and xx are integers. For example, “C₁₋₄ alkyl” isan alkyl group which has from 1 to 4 carbon atoms; “C₁₋₆ alkyl” is analkyl group having from 1 to 6 carbon atoms; and “C₆₋₁₀ aryl” is an arylgroup which has from 6 to 10 carbon atoms.

4. BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 depicts mean ALCs (±SE) over time. ALC=absolute lymphocyte count;SE=standard error; BL=baseline; LLN=lower limit of normal.

FIG. 2 depicts mean ALCs over time in patients with ALCs less than500/mm³ persisting for greater than or equal to 6 months versus allother patients. Shaded area in top panel is expanded in bottom panel.ALC=absolute lymphocyte count; SE=standard error. ^(a)DMF isdelayed-release DMF (also known as gastro-resistant DMF, and asTECFIDERA®). ^(b)Baseline (Week 0) n includes all patients for whom abaseline ALC value was available. ^(c)Mean ALCs over time are presentedout to approximately 5 years (week 240), as this is the minimumfollow-up for patients remaining on study in ENDORSE.

FIG. 3 depicts that ALCs generally increased post-dosing in the 4 weeksfollowing discontinuation of treatment in 9 patients with ALCs less than500 cells/μL for at least 6 months. ALC=absolute lymphocyte count;BID=twice daily; LLN=lower limit of normal; TID=three timers daily.^(a)DMF is delayed-release DMF (also known as gastro-resistant DMF, andas)TECFIDERA®.

FIGS. 4A-4B depict reduction in ARR at 2 years in DEFINE (FIG. 4A) andCONFIRM (FIG. 4B) in patients in the DMF BID group with lymphopenia (atleast 1 ALC less than LLN) or without lymphopenia (all ALCs greater thanor equal to LLN) compared with all patients in placebo group.ARR=annualized relapse rate; CI=confidence interval. ^(a)DMF isdelayed-release DMF (also known as gastro-resistant DMF, and asTECFIDERA®). ^(b)Based on negative binomial regression, adjusted forstudy, baseline EDSS (≦2.0 vs>2.0), baseline age (<40 vs>40), region,and number of relapses in the 1 year prior to study entry.

5. DETAILED DESCRIPTION

The invention provides methods of treating a patient with MS, andimproving safety in treatment with MS, based on the recognition of PMLas a complication of treatment with the fumarates described herein insome patients. One fatal case of progressive multifocalleukoencephalopathy (PML) occurred in a patient with MS who receivedTECFIDERA® for 4 years while enrolled in a clinical trial. The patientreceiving TECFIDERA® had not previously been treated withimmunosuppressive medications or natalizumab, which has a knownassociation with PML, and had no identified systemic medical conditionsresulting in compromised immune system function. The patient was alsonot taking any immunosuppressive or immunomodulatory medicationsconcomitantly. During the clinical trial, the patient experiencedprolonged lymphopenia (lymphocyte counts predominantly less than0.5×10⁹/L for 3.5 years) while taking TECFIDERA®.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a fumarate to the patient,wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, acombination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug ofmonoalkyl fumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; and (b) monitoring the patient for a sign or symptomsuggestive of PML in the patient.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising monitoring a patient withmultiple sclerosis who is being treated with a fumarate for a sign orsymptom suggestive of PML in the patient, wherein the fumarate is adialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a pharmaceuticallyacceptable salt, clathrate, solvate, tautomer, or stereoisomer of any ofthe foregoing, or a combination of any of the foregoing.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a fumarate to the patient,wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, acombination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug ofmonoalkyl fumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; and (b) informing the patient that PML has occurred in apatient who received dimethyl fumarate.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a fumarate to the patient,wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, acombination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug ofmonoalkyl fumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; and (b) instructing the patient of the importance ofcontacting the patient's doctor if the patient develops any symptomssuggestive of PML.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising informing a patient withmultiple sclerosis who is being treated with a fumarate that PML hasoccurred in a patient who received dimethyl fumarate, wherein thefumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of adialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising instructing a patient withmultiple sclerosis who is being treated with a fumarate of theimportance of contacting the patient's doctor if the patient developsany symptoms suggestive of PML, wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that a fumarate salt is not present in thepharmaceutical composition; and (b) monitoring the patient for a sign orsymptom suggestive of PML in the patient.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising monitoring a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate for a sign or symptom suggestive ofPML in the patient; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a clathrate, solvate, tautomer, or stereoisomer of anyof the foregoing, or a combination of any of the foregoing; with theproviso that a fumarate salt is not present in the pharmaceuticalcomposition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that a fumarate salt is not present in thepharmaceutical composition; and (b) informing the patient that PML hasoccurred in a patient who received dimethyl fumarate.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that a fumarate salt is not present in thepharmaceutical composition; and (b) instructing the patient of theimportance of contacting the patient's doctor if the patient developsany symptoms suggestive of PML.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising informing a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate that PML has occurred in a patient whoreceived dimethyl fumarate; wherein the fumarate is a dialkyl fumarate,a monoalkyl fumarate, a combination of a dialkyl fumarate and amonoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that a fumarate salt is not present in thepharmaceutical composition.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising instructing a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate of the importance of contacting thepatient's doctor if the patient develops any symptoms suggestive of PML;wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, acombination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug ofmonoalkyl fumarate, a deuterated form of any of the foregoing, or aclathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that afumarate salt is not present in the pharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that an ethylhydrogen fumarate salt is not present in the pharmaceutical composition;and (b) monitoring the patient for a sign or symptom suggestive of PMLin the patient.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising monitoring a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate for a sign or symptom suggestive ofPML in the patient; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a pharmaceutically acceptable salt, clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing; with the proviso that an ethylhydrogen fumarate salt is not present in the pharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that an ethylhydrogen fumarate salt is not present in the pharmaceutical composition;and (b) informing the patient that PML has occurred in a patient whoreceived dimethyl fumarate.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that an ethylhydrogen fumarate salt is not present in the pharmaceutical composition;and (b) instructing the patient of the importance of contacting thepatient's doctor if the patient develops any symptoms suggestive of PML.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising informing a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate that PML has occurred in a patient whoreceived dimethyl fumarate; wherein the fumarate is a dialkyl fumarate,a monoalkyl fumarate, a combination of a dialkyl fumarate and amonoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that an ethylhydrogen fumarate salt is not present in the pharmaceutical composition.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising instructing a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate of the importance of contacting thepatient's doctor if the patient develops any symptoms suggestive of PML;wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, acombination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug ofmonoalkyl fumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that an ethyl hydrogen fumarate salt is notpresent in the pharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition; and (b)monitoring the patient for a sign or symptom suggestive of PML in thepatient.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising monitoring a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate for a sign or symptom suggestive ofPML in the patient; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a pharmaceutically acceptable salt, clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition; and (b)informing the patient that PML has occurred in a patient who receiveddimethyl fumarate.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition; and (b)instructing the patient of the importance of contacting the patient'sdoctor if the patient develops any symptoms suggestive of PML.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising informing a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate that PML has occurred in a patient whoreceived dimethyl fumarate; wherein the fumarate is a dialkyl fumarate,a monoalkyl fumarate, a combination of a dialkyl fumarate and amonoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising instructing a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate of the importance of contacting thepatient's doctor if the patient develops any symptoms suggestive of PML;wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, acombination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug ofmonoalkyl fumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that ethyl hydrogen fumarate calcium salt,ethyl hydrogen fumarate magnesium salt, ethyl hydrogen fumarate zincsalt, and ethyl hydrogen fumarate copper salt are not present in thepharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositionconsisting essentially of dimethyl fumarate and/or monomethyl fumarateto the patient; and (b) monitoring the patient for a sign or symptomsuggestive of PML in the patient.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising monitoring a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition consisting essentially of dimethyl fumarate and/ormonomethyl fumarate for a sign or symptom suggestive of PML in thepatient.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositionconsisting essentially of dimethyl fumarate and/or monomethyl fumarateto the patient; and (b) informing the patient that PML has occurred in apatient who received dimethyl fumarate.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositionconsisting essentially of dimethyl fumarate and/or monomethyl fumarateto the patient; and (b) instructing the patient of the importance ofcontacting the patient's doctor if the patient develops any symptomssuggestive of PML.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising informing a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition consisting essentially of dimethyl fumarate and/ormonomethyl fumarate that PML has occurred in a patient who receiveddimethyl fumarate.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising instructing a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition consisting essentially of dimethyl fumarate and/ormonomethyl fumarate of the importance of contacting the patient's doctorif the patient develops any symptoms suggestive of PML.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a fumarate to the patient,wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, acombination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug ofmonoalkyl fumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; and (b) obtaining a complete blood count including lymphocytecount after 6 months of repeated administering of said pharmaceuticalcomposition to said patient, and every 6 to 12 months thereafter.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that a fumarate salt is not present in thepharmaceutical composition; and (b) obtaining a complete blood countincluding lymphocyte count after 6 months of repeated administering ofsaid pharmaceutical composition to said patient, and every 6 to 12months thereafter.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that an ethylhydrogen fumarate salt is not present in the pharmaceutical composition;and (b) obtaining a complete blood count including lymphocyte countafter 6 months of repeated administering of said pharmaceuticalcomposition to said patient, and every 6 to 12 months thereafter.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition; and (b)obtaining a complete blood count including lymphocyte count after 6months of repeated administering of said pharmaceutical composition tosaid patient, and every 6 to 12 months thereafter.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositionconsisting essentially of dimethyl fumarate and/or monomethyl fumarateto the patient; and (b) obtaining a complete blood count includinglymphocyte count after 6 months of repeated administering of saidpharmaceutical composition to said patient, and every 6 to 12 monthsthereafter.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) prior to initiating treatment of the patientwith a pharmaceutical composition comprising a fumarate: (i) performinga complete blood count including lymphocyte count; and (ii) if thelymphocyte count is found to be below the normal range, consideringalternative causes of lymphopenia, and taking corrective measures asappropriate regarding said alternative causes; and (b) administeringsaid pharmaceutical composition to the patient, wherein the fumarate isa dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a pharmaceuticallyacceptable salt, clathrate, solvate, tautomer, or stereoisomer of any ofthe foregoing, or a combination of any of the foregoing.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) repeatedly administering a pharmaceuticalcomposition comprising a fumarate to the patient; wherein the fumarateis a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a pharmaceuticallyacceptable salt, clathrate, solvate, tautomer, or stereoisomer of any ofthe foregoing, or a combination of any of the foregoing; and (b)obtaining a complete blood count including lymphocyte count every 3months after starting therapy of said patient with said pharmaceuticalcomposition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; and (b) monitoring the patientclosely for signs or symptoms of appearance of new neurologicaldysfunction if the patient experiences lymphopenia after administeringof said pharmaceutical composition.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising monitoring a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate, and who experiences lymphopenia, forsigns or symptoms of appearance of new neurological dysfunction; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing.

Provided herein is a method of treating multiple sclerosis in a patientwho is being treated with a multiple sclerosis disease-modifying therapyother than a pharmaceutical composition comprising a fumarate; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; said method comprising the following steps in the statedorder: (a) stopping administration of said multiple sclerosisdisease-modifying therapy to said patient; (b) considering the half-lifeand mode of action of said multiple sclerosis disease-modifying therapyin order to avoid an additive immune effect whilst at the same timeminimizing the risk of disease reactivation; and (c) administering thepharmaceutical composition comprising the fumarate to the patient.

Provided herein is a method of treating multiple sclerosis in a patientwho is being treated with interferon or glatiramer acetate, said methodcomprising (a) discontinuing administration of interferon or glatirameracetate to the patient; and (b) immediately after said discontinuing,starting administering to the patient of a pharmaceutical compositioncomprising a fumarate; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a pharmaceutically acceptable salt, clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; and (b) prior to the initialadministering of the pharmaceutical composition comprising the fumarateto the patient, and periodically during treatment of said patient withsaid pharmaceutical composition comprising the fumarate, having a bloodtest done to count the number of white blood cells in the patient; and(c) considering stopping said treatment with said pharmaceuticalcomposition comprising the fumarate if the number of white blood cellsdecreases during said treatment.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) prior to initiating treatment of the patientwith a pharmaceutical composition comprising a fumarate: (i) performinga complete blood count including lymphocyte count; and (ii) if thelymphocyte count is found to be below the normal range, consideringalternative causes of lymphopenia, and taking corrective measures asappropriate regarding said alternative causes; and (b) administeringsaid pharmaceutical composition to the patient, wherein the fumarate isa dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a clathrate, solvate,tautomer, or stereoisomer of any of the foregoing, or a combination ofany of the foregoing; with the proviso that a fumarate salt is notpresent in the pharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) repeatedly administering a pharmaceuticalcomposition comprising a fumarate to the patient; wherein the fumarateis a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a clathrate, solvate,tautomer, or stereoisomer of any of the foregoing, or a combination ofany of the foregoing; with the proviso that a fumarate salt is notpresent in the pharmaceutical composition; and (b) obtaining a completeblood count including lymphocyte count every 3 months after startingtherapy of said patient with said pharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that a fumarate salt is not present in thepharmaceutical composition; and (b) monitoring the patient closely forsigns or symptoms of appearance of new neurological dysfunction if thepatient experiences lymphopenia after administering of saidpharmaceutical composition.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising monitoring a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate, and who experiences lymphopenia, forsigns or symptoms of appearance of new neurological dysfunction; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or a clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing; with the proviso that a fumaratesalt is not present in the pharmaceutical composition.

Provided herein is a method of treating multiple sclerosis in a patientwho is being treated with a multiple sclerosis disease-modifying therapyother than a pharmaceutical composition comprising a fumarate; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or a clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing; with the proviso that a fumaratesalt is not present in the pharmaceutical composition; said methodcomprising the following steps in the stated order: (a) stoppingadministration of said multiple sclerosis disease-modifying therapy tosaid patient; (b) considering the half-life and mode of action of saidmultiple sclerosis disease-modifying therapy in order to avoid anadditive immune effect whilst at the same time minimizing the risk ofdisease reactivation; and (c) administering the pharmaceuticalcomposition comprising the fumarate to the patient.

Provided herein is a method of treating multiple sclerosis in a patientwho is being treated with interferon or glatiramer acetate, said methodcomprising (a) discontinuing administration of interferon or glatirameracetate to the patient; and (b) immediately after said discontinuing,starting administering to the patient of a pharmaceutical compositioncomprising a fumarate; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a clathrate, solvate, tautomer, or stereoisomer of anyof the foregoing, or a combination of any of the foregoing; with theproviso that a fumarate salt is not present in the pharmaceuticalcomposition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that a fumarate salt is not present in thepharmaceutical composition; and (b) prior to the initial administeringof the pharmaceutical composition comprising the fumarate to thepatient, and periodically during treatment of said patient with saidpharmaceutical composition comprising the fumarate, having a blood testdone to count the number of white blood cells in the patient; and (c)considering stopping said treatment with said pharmaceutical compositioncomprising the fumarate if the number of white blood cells decreasesduring said treatment.

Provided herein is a A method of treating a patient with multiplesclerosis comprising (a) prior to initiating treatment of the patientwith a pharmaceutical composition comprising a fumarate: (i) performinga complete blood count including lymphocyte count; and (ii) if thelymphocyte count is found to be below the normal range, consideringalternative causes of lymphopenia, and taking corrective measures asappropriate regarding said alternative causes; and (b) administeringsaid pharmaceutical composition to the patient, wherein the fumarate isa dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a pharmaceuticallyacceptable salt, clathrate, solvate, tautomer, or stereoisomer of any ofthe foregoing, or a combination of any of the foregoing; with theproviso that an ethyl hydrogen fumarate salt is not present in thepharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) repeatedly administering a pharmaceuticalcomposition comprising a fumarate to the patient; wherein the fumarateis a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a pharmaceuticallyacceptable salt, clathrate, solvate, tautomer, or stereoisomer of any ofthe foregoing, or a combination of any of the foregoing; with theproviso that an ethyl hydrogen fumarate salt is not present in thepharmaceutical composition; and (b) obtaining a complete blood countincluding lymphocyte count every 3 months after starting therapy of saidpatient with said pharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that an ethylhydrogen fumarate salt is not present in the pharmaceutical composition;and (b) monitoring the patient closely for signs or symptoms ofappearance of new neurological dysfunction if the patient experienceslymphopenia after administering of said pharmaceutical composition.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising monitoring a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate, and who experiences lymphopenia, forsigns or symptoms of appearance of new neurological dysfunction; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that an ethyl hydrogen fumarate salt is notpresent in the pharmaceutical composition.

Provided herein is a method of treating multiple sclerosis in a patientwho is being treated with a multiple sclerosis disease-modifying therapyother than a pharmaceutical composition comprising a fumarate; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that an ethyl hydrogen fumarate salt is notpresent in the pharmaceutical composition; said method comprising thefollowing steps in the stated order: (a) stopping administration of saidmultiple sclerosis disease-modifying therapy to said patient; (b)considering the half-life and mode of action of said multiple sclerosisdisease-modifying therapy in order to avoid an additive immune effectwhilst at the same time minimizing the risk of disease reactivation; and(c) administering the pharmaceutical composition comprising the fumarateto the patient.

Provided herein is a method of treating multiple sclerosis in a patientwho is being treated with interferon or glatiramer acetate, said methodcomprising (a) discontinuing administration of interferon or glatirameracetate to the patient; and (b) immediately after said discontinuing,starting administering to the patient of a pharmaceutical compositioncomprising a fumarate; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a pharmaceutically acceptable salt, clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing; with the proviso that an ethylhydrogen fumarate salt is not present in the pharmaceutical composition.

Provided herein is a A method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that an ethylhydrogen fumarate salt is not present in the pharmaceutical composition;and (b) prior to the initial administering of the pharmaceuticalcomposition comprising the fumarate to the patient, and periodicallyduring treatment of said patient with said pharmaceutical compositioncomprising the fumarate, having a blood test done to count the number ofwhite blood cells in the patient; and (c) considering stopping saidtreatment with said pharmaceutical composition comprising the fumarateif the number of white blood cells decreases during said treatment.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) prior to initiating treatment of the patientwith a pharmaceutical composition comprising a fumarate: (i) performinga complete blood count including lymphocyte count; and (ii) if thelymphocyte count is found to be below the normal range, consideringalternative causes of lymphopenia, and taking corrective measures asappropriate regarding said alternative causes; and (b) administeringsaid pharmaceutical composition to the patient, wherein the fumarate isa dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a pharmaceuticallyacceptable salt, clathrate, solvate, tautomer, or stereoisomer of any ofthe foregoing, or a combination of any of the foregoing; with theproviso that ethyl hydrogen fumarate calcium salt, ethyl hydrogenfumarate magnesium salt, ethyl hydrogen fumarate zinc salt, and ethylhydrogen fumarate copper salt are not present in the pharmaceuticalcomposition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) repeatedly administering a pharmaceuticalcomposition comprising a fumarate to the patient; wherein the fumarateis a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a pharmaceuticallyacceptable salt, clathrate, solvate, tautomer, or stereoisomer of any ofthe foregoing, or a combination of any of the foregoing; with theproviso that ethyl hydrogen fumarate calcium salt, ethyl hydrogenfumarate magnesium salt, ethyl hydrogen fumarate zinc salt, and ethylhydrogen fumarate copper salt are not present in the pharmaceuticalcomposition; and (b) obtaining a complete blood count includinglymphocyte count every 3 months after starting therapy of said patientwith said pharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition; and (b)monitoring the patient closely for signs or symptoms of appearance ofnew neurological dysfunction if the patient experiences lymphopeniaafter administering of said pharmaceutical composition.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising monitoring a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate, and who experiences lymphopenia, forsigns or symptoms of appearance of new neurological dysfunction; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that ethyl hydrogen fumarate calcium salt,ethyl hydrogen fumarate magnesium salt, ethyl hydrogen fumarate zincsalt, and ethyl hydrogen fumarate copper salt are not present in thepharmaceutical composition.

Provided herein is a method of treating multiple sclerosis in a patientwho is being treated with a multiple sclerosis disease-modifying therapyother than a pharmaceutical composition comprising a fumarate; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that ethyl hydrogen fumarate calcium salt,ethyl hydrogen fumarate magnesium salt, ethyl hydrogen fumarate zincsalt, and ethyl hydrogen fumarate copper salt are not present in thepharmaceutical composition; said method comprising the following stepsin the stated order: (a) stopping administration of said multiplesclerosis disease-modifying therapy to said patient; (b) considering thehalf-life and mode of action of said multiple sclerosisdisease-modifying therapy in order to avoid an additive immune effectwhilst at the same time minimizing the risk of disease reactivation; and(c) administering the pharmaceutical composition comprising the fumarateto the patient.

Provided herein is a method of treating multiple sclerosis in a patientwho is being treated with interferon or glatiramer acetate, said methodcomprising (a) discontinuing administration of interferon or glatirameracetate to the patient; and (b) immediately after said discontinuing,starting administering to the patient of a pharmaceutical compositioncomprising a fumarate; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a pharmaceutically acceptable salt, clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition; and (b) prior tothe initial administering of the pharmaceutical composition comprisingthe fumarate to the patient, and periodically during treatment of saidpatient with said pharmaceutical composition comprising the fumarate,having a blood test done to count the number of white blood cells in thepatient; and (c) considering stopping said treatment with saidpharmaceutical composition comprising the fumarate if the number ofwhite blood cells decreases during said treatment.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) prior to initiating treatment of the patientwith a pharmaceutical composition consisting essentially of dimethylfumarate and/or monomethyl fumarate: (i) performing a complete bloodcount including lymphocyte count; and (ii) if the lymphocyte count isfound to be below the normal range, considering alternative causes oflymphopenia, and taking corrective measures as appropriate regardingsaid alternative causes; and (b) administering said pharmaceuticalcomposition to the patient.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) repeatedly administering a pharmaceuticalcomposition consisting essentially of dimethyl fumarate and/ormonomethyl fumarate to the patient; and (b) obtaining a complete bloodcount including lymphocyte count every 3 months after starting therapyof said patient with said pharmaceutical composition.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositionconsisting essentially of dimethyl fumarate and/or monomethyl fumarateto the patient; and (b) monitoring the patient closely for signs orsymptoms of appearance of new neurological dysfunction if the patientexperiences lymphopenia after administering of said pharmaceuticalcomposition.

Provided herein is a method of improving safety in treatment of apatient with multiple sclerosis comprising monitoring a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition consisting essentially of dimethyl fumarate and/ormonomethyl fumarate, and who experiences lymphopenia, for signs orsymptoms of appearance of new neurological dysfunction.

Provided herein is a method of treating multiple sclerosis in a patientwho is being treated with a multiple sclerosis disease-modifying therapyother than a pharmaceutical composition consisting essentially ofdimethyl fumarate and/or monomethyl fumarate; said method comprising thefollowing steps in the stated order: (a) stopping administration of saidmultiple sclerosis disease-modifying therapy to said patient; (b)considering the half-life and mode of action of said multiple sclerosisdisease-modifying therapy in order to avoid an additive immune effectwhilst at the same time minimizing the risk of disease reactivation; and(c) administering the pharmaceutical composition consisting essentiallyof dimethyl fumarate and/or monomethyl fumarate.

Provided herein is a method of treating multiple sclerosis in a patientwho is being treated with interferon or glatiramer acetate, said methodcomprising (a) discontinuing administration of interferon or glatirameracetate to the patient; and (b) immediately after said discontinuing,starting administering a pharmaceutical composition consistingessentially of dimethyl fumarate and/or monomethyl fumarate to thepatient.

Provided herein is a method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositionconsisting essentially of dimethyl fumarate and/or monomethyl fumarateto the patient; and (b) prior to the initial administering of saidpharmaceutical composition to the patient, and periodically duringtreatment of said patient with said pharmaceutical composition, having ablood test done to count the number of white blood cells in the patient;and (c) considering stopping said treatment with said pharmaceuticalcomposition if the number of white blood cells decreases during saidtreatment.

All of the various aspects, embodiments, and options disclosed hereincan be combined in any and all variations. The compositions and methodsprovided are exemplary and are not intended to limit the scope of theclaimed embodiments.

5.1 Active Agents for Use in the Methods Provided Herein

The active agents (i.e., drugs) for use in the methods and compositionsof the invention are fumarates. Such a fumarate can be a dialkylfumarate (e.g., dimethyl fumarate), a monoalkyl fumarate (e.g.,monomethyl fumarate), a combination of dialkyl and monoalkyl fumarates(e.g., dimethyl fumarate and monomethyl fumarate), a prodrug ofmonoalkyl (e.g., monomethyl) fumarate, a deuterated form of any of theforegoing, or a pharmaceutically acceptable salt, clathrate, solvate,tautomer, or stereoisomer of any of the foregoing, or a combination ofany of the foregoing. In one embodiment, the fumarate used in themethods, compositions and products described in this specification isdimethyl fumarate. In a specific embodiment, the fumarate is (i) amonoalkyl fumarate or prodrug thereof, or (ii) a dialkyl fumarate. Inone embodiment, the monoalkylfumarate is monomethyl fumarate (“MMF”). Inanother embodiment, the dialkyl fumarate is dimethyl fumarate (“DMF”).

5.1.1 Mono- and Dialkyl Fumarates

In particular, provided herein are mono- and dialkyl fumarates orpharmaceutically acceptable salts, clathrates, solvates, orstereoisomers thereof for use in the methods provided herein.

In one embodiment, the fumarate is a monoalkyl fumarate of Formula I:

-   -   or a pharmaceutically acceptable salt, clathrate, solvate, or        stereoisomer thereof, wherein    -   R¹ is C₁₋₆ alkyl.

In certain embodiments of a compound of Formula (I), R¹ is methyl(monomethyl fumarate, “MMF”).

In one embodiment, the compounds of Formula I may be prepared usingmethods known to those skilled in the art, for example, as disclosed inU.S. Pat. No. 4,959,389.

In another embodiment, the fumarate is a dialkyl fumarate of Formula II:

-   -   or a pharmaceutically acceptable salt, clathrate, solvate, or        stereoisomer thereof, wherein    -   each R² is independently C₁₋₆ alkyl.

In certain embodiments of a compound of Formula (II), each R² is methyl(dimethyl fumarate, “DMF”). In a specific embodiment, the agent isadministered as a pharmaceutical composition, wherein the pharmaceuticalcomposition is TECFIDERA®. In another specific embodiment, the agent isas a pharmaceutical composition, wherein the pharmaceutical compositionis FUMADERM®. FUMADERM® comprises of the following active ingredients:dimethyl fumarate, calcium salt of ethyl hydrogen fumarate, magnesiumsalt of ethyl hydrogen fumarate, and zinc salt of ethyl hydrogenfumarate.

In one embodiment, the compounds of Formula (II) may be prepared usingmethods known to those skilled in the art, for example, as disclosed inU.S. Pat. No. 4,959,389.

In one embodiment, the fumarate is dimethyl fumarate and/or monomethylfumarate.

In one embodiment, the fumarate is dimethyl fumarate

5.1.2 Prodrugs of Monoalkyl Fumarates

Further provided herein are prodrugs of monoalkyl fumarates orpharmaceutically acceptable salts, clathrates, solvates, orstereoisomers thereof for use in the methods provided herein.

In particular, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in WO2013/119677, such as the compounds of Formula (III):

-   -   or a pharmaceutically acceptable salt, clathrate, solvate,        tautomer, or stereoisomer thereof,    -   R³ is C₁₋₆ alkyl;    -   R⁴ and R⁵ are each independently hydrogen, C₁₋₆ alkyl, or        substituted C₁₋₆ alkyl;    -   R⁶ and R⁷ are each independently hydrogen, C₁₋₆ alkyl,        substituted C₁₋₆ alkyl, C₁₋₆ heteroalkyl, substituted C₁₋₆        heteroalkyl, C₄₋₁₂ cycloalkylalkyl, substituted C₄₋₁₂        cycloalkylalkyl, C₇₋₁₂ arylalkyl, or substituted C₇₋₁₂        arylalkyl; or R⁶ and R⁷ together with the nitrogen to which they        are attached form a ring chosen from C₅₋₁₀ heteroaryl,        substituted C₅₋₁₀ heteroaryl, C₅₋₁₀ heterocycloalkyl, and        substituted C₅₋₁₀ heterocycloalkyl; and    -   wherein each substituent is independently halogen, —OH, —CN,        —CF₃, ═O, —NO₂, benzyl, —C(O)NR⁸ ₂, —R⁸, —OR⁸, —C(O)R⁸,        —COOR^(S), or —NR⁸ ₂ wherein each R⁸ is independently hydrogen        or C₁₋₄ alkyl.

In certain embodiments of a compound of Formula (III), when R³ is ethyl;then R⁶ and R⁷ are each independently hydrogen, C₁₋₆ alkyl, orsubstituted C₁₋₆ alkyl.

In certain embodiments of a compound of Formula (III), each substituentgroup is independently halogen, —OH, —CN, —CF₃, —R⁸, —OR⁸, or —NR⁸ ₂wherein each R⁸ is independently hydrogen or C₁₋₄ alkyl. In certainembodiments, each substituent group is independently —OH or —COOH.

In certain embodiments of a compound of Formula (III), each substituentgroup is independently ═O, C₁₋₄ alkyl, or —COOR⁸, wherein R⁸ is hydrogenor C₁₋₄ alkyl.

In certain embodiments of a compound of Formula (III), R³ is methyl.

In certain embodiments of a compound of Formula (III), R³ is ethyl.

In certain embodiments of a compound of Formula (III), R³ is C₃₋₆ alkyl.

In certain embodiments of a compound of Formula (III), R³ is methyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

In certain embodiments of a compound of Formula (III), R³ is methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

In certain embodiments of a compound of Formula (III), each of R⁴ and R⁵is hydrogen.

In certain embodiments of a compound of Formula (III), one of R⁴ and R⁵is hydrogen and the other of R⁴ and R⁵ is C₁₋₄ alkyl.

In certain embodiments of a compound of Formula (III), one of R⁴ and R⁵is hydrogen and the other of R⁴ and R⁵ is methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec- butyl, or tert-butyl.

In certain embodiments of a compound of Formula (III), one of R⁴ and R⁵is hydrogen and the other of R⁴ and R⁵ is methyl.

In certain embodiments of a compound of Formula (III), R⁶ and R⁷ areeach independently hydrogen or C₁₋₆ alkyl.

In certain embodiments of a compound of Formula (III), R⁶ and R⁷ areeach independently hydrogen or C₁₋₄ alkyl.

In certain embodiments of a compound of Formula (III), R⁶ and R⁷ areeach independently hydrogen, methyl, or ethyl.

In certain embodiments of a compound of Formula (III), R⁶ and R⁷ areeach hydrogen; in certain embodiments, R⁶ and R⁷ are each methyl; and incertain embodiments, R⁶ and R⁷ are each ethyl.

In certain embodiments of a compound of Formula (III), R⁶ is hydrogen;and R⁷ is C₁₋₄ alkyl, substituted C₁₋₄ alkyl wherein each substituentindependently is ═O, —OR⁸, —COOR⁸, or —NR⁸ ₂, and wherein each R⁸ isindependently hydrogen or C₁₋₄ alkyl.

In certain embodiments of a compound of Formula (III), R⁶ is hydrogen;and R⁷ is C₁₋₄ alkyl, benzyl, 2-methoxyethyl, carboxymethyl,carboxypropyl, 1,3,4-thiadiazolyl, methoxy, —COOCH₃,2-oxo-1,3-oxazolidinyl, 2-(methylethoxy)ethyl, 2-ethoxyethyl,(tert-butyloxycarbonyl)methyl, (ethoxycarbonyl)methyl,(methylethyl)oxycarbonylmethyl, or ethoxycarbonylmethyl.

In certain embodiments of a compound of Formula (III), R⁶ and R⁷together with the nitrogen to which they are attached form a ring chosenfrom a C₅₋₆ heterocycloalkyl, substituted C₅₋₆ heterocycloalkyl, C₅₋₆heteroaryl, and substituted C₅₋₆ heteroaryl ring. In certain embodimentsof a compound of Formula (III), R⁶ and R⁷ together with the nitrogen towhich they are attached form a ring chosen from a C₅ heterocycloalkyl,substituted C₅ heterocycloalkyl, C₅ heteroaryl, and substituted C₅heteroaryl ring. In certain embodiments of a compound of Formula (III),R⁶ and R⁷ together with the nitrogen to which they are attached form aring chosen from a C₆ heterocycloalkyl, substituted C₆ heterocycloalkyl,C₆ heteroaryl, and substituted C₆ heteroaryl ring. In certainembodiments of a compound of Formula (III), R⁶ and R⁷ together with thenitrogen to which they are attached form a ring chosen from piperazine,1,3-oxazolidinyl, pyrrolidine, and morpholine ring.

In certain embodiments of a compound of Formula (III), R⁶ and R⁷together with the nitrogen to which they are attached form a C₅₋₁₀heterocycloalkyl ring.

In certain embodiments of a compound of Formula (III), one of R⁴ and R⁵is hydrogen and the other of R⁴ and R⁵ is C₁₋₆ alkyl; R⁶ is hydrogen; R⁷is hydrogen, C₁₋₆ alkyl, or benzyl.

In certain embodiments of a compound of Formula (III), R³ is methyl; oneof R⁴ and R⁵ is hydrogen and the other of R⁴ and R⁵ is C₁₋₆ alkyl; R⁶ ishydrogen; and R⁷ is hydrogen, C₁₋₆ alkyl, or benzyl.

In certain embodiments of a compound of Formula (III), one of R⁴ and R⁵is hydrogen and the other of R⁴ and R⁵ is hydrogen or C₁₋₆ alkyl; andeach of R⁶ and R⁷ is C₁₋₆ alkyl.

In certain embodiments of a compound of Formula (III), R³ is methyl; oneof R⁴ and R⁵ is hydrogen and the other of R⁴ and R⁵ is hydrogen or C₁₋₆alkyl; and each of R⁶ and R⁷ is C₁₋₆ alkyl. In certain embodiments of acompound of Formula (III), R⁵ is methyl; each of R⁴ and R⁵ is hydrogen;and each of R⁶ and R⁷ is C₁₋₆ alkyl.

In certain embodiments of a compound of Formula (III), R³ is methyl; oneof R⁴ and R⁵ is hydrogen and the other of R⁴ and R⁵ is hydrogen or C₁₋₄alkyl; R⁶ is hydrogen; and R⁷ is C₁₋₄ alkyl or substituted C₁₋₄ alkylwherein the substituent group is ═O, —OR⁸, —COOR⁸, or —NR⁸ ₂, whereineach R⁸ is independently hydrogen or C₁₋₄ alkyl. In certain embodimentsof a compound of Formula (III), R³ is methyl; one of R⁴ and R⁵ ishydrogen and the other of R⁴ and R⁵ is methyl; R⁶ is hydrogen; and R⁷ isC₁₋₄ alkyl or substituted C₁₋₄ alkyl wherein the substituent group is═O, —OR⁸, —COOR⁸, or —NR⁸ ₂, wherein each R⁸ is independently hydrogenor C₁₋₄ alkyl. In certain embodiments of a compound of Formula (III), R³is methyl; each of R⁴ and R⁵ is hydrogen; R⁶ is hydrogen; and R⁷ is C₁₋₄alkyl or substituted C₁₋₄ alkyl wherein the substituent group is ═O,—OR¹¹, —COOR¹¹, or —NR¹¹ ₂, wherein each R¹¹ is independently hydrogenor C₁₋₄ alkyl.

In certain embodiments of a compound of Formula (III), R⁶ and R⁷together with the nitrogen to which they are attached form a C₅₋₁₀heterocycloalkyl ring.

In certain embodiments of a compound of Formula (III), R³ is methyl; oneof R⁴ and R⁵ is hydrogen and the other of R⁴ and R⁵ is hydrogen or C₁₋₆alkyl; and R⁶ and R⁷ together with the nitrogen to which they areattached form a ring chosen from C₅₋₆ heterocycloalkyl, substituted C₅₋₆heterocycloalkyl, C₅₋₆ heteroaryl, and substituted C₅₋₆ heteroaryl ring.In certain embodiments of a compound of Formula (III), R³ is methyl; oneof R⁴ and R⁵ is hydrogen and the other of R⁴ and R⁵ is methyl; R⁶ and R⁷together with the nitrogen to which they are attached form a ring chosenfrom a C₅₋₆ heterocycloalkyl, substituted C₅₋₆ heterocycloalkyl, C₅₋₆heteroaryl, and substituted C₅₋₆ heteroaryl ring. In certain embodimentsof a compound of Formula (III), R³ is methyl; each of R⁴ and R⁵ ishydrogen; and R⁶ and R⁷ together with the nitrogen to which they areattached form a ring chosen from C₅₋₆ heterocycloalkyl, substituted C₅₋₆heterocycloalkyl, C₅₋₆ heteroaryl, and substituted C₅₋₆ heteroaryl ring.

In certain embodiments of a compound of Formula (III), one of R⁴ and R⁵is hydrogen and the other of R⁴ and R⁵ is hydrogen or C₁₋₆ alkyl; and R⁶and R⁷ together with the nitrogen to which they are attached form a ringchosen from morpholine, piperazine, and N-substituted piperazine.

In certain embodiments of a compound of Formula (III), R³ is methyl; oneof R⁴ and R⁵ is hydrogen and the other of R⁴ and R⁵ is hydrogen or C₁₋₆alkyl; and R⁶ and R⁷ together with the nitrogen to which they areattached form a ring chosen from morpholine, piperazine, andN-substituted piperazine.

In certain embodiments of a compound of Formula (III), R³ is not methyl.

In certain embodiments of a compound of Formula (III), R⁴ is hydrogen,and in certain embodiments, R⁵ is hydrogen.

In certain embodiments of a compound of Formula (III), R⁶ and R⁷ areindependently hydrogen, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₆₋₁₀ aryl,substituted C₆₋₁₀ aryl, C₄₋₁₂cycloalkylalkyl, substitutedC₄₋₁₂cycloalkylalkyl, C₇₋₁₂ arylalkyl, substituted C₇₋₁₂ arylalkyl, C₁₋₆heteroalkyl, substituted C₁₋₆ heteroalkyl, C₆₋₁₀ heteroaryl, substitutedC₆₋₁₀ heteroaryl, C₄₋₁₂heterocycloalkylalkyl, substitutedC₄₋₁₂heterocycloalkylalkyl, C₇₋₁₂ heteroarylalkyl, substituted C₇₋₁₂heteroarylalkyl; or R⁶ and R⁷ together with the nitrogen to which theyare attached form a ring chosen from a C₅₋₁₀ heteroaryl, substitutedC₅₋₁₀ heteroaryl, C₅₋₁₀ heterocycloalkyl, and substituted C₅₋₁₀heterocycloalkyl.

In certain embodiments of a compound of Formula (III), the compound is:

-   (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate;-   methyl[N-benzylcarbamoyl]methyl(2E)but-2-ene-1,4-dioate;-   methyl 2-morpholin-4-yl-2-oxoethyl(2E)but-2-ene-1,4-dioate;-   (N-butylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate;-   [N-(2-methoxyethyl)carbamoyl]methyl methyl(2E)but-2-ene-1,4-dioate;-   2-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}acetic    acid;-   4-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}butanoic    acid;-   methyl(N-(1,3,4-thiadiazol-2-yl)carbamoyl)methyl(2E)but-2ene-1,4-dioate;-   (N,N-dimethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate;-   (N-methoxy-N-methylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate;-   bis-(2-methoxyethylamino)carbamoyl]methyl    methyl(2E)but-2-ene-1,4-dioate;-   [N-(methoxycarbonyl)carbamoyl]methyl methyl(2E)but-2ene-1,4-dioate;-   4-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}butanoic    acid, sodium salt;-   methyl 2-oxo-2-piperazinylethyl(2E)but-2-ene-1,4-dioate;-   methyl    2-oxo-2-(2-oxo(1,3-oxazolidin-3-yl)ethyl(2E)but-2ene-1,4-dioate;-   {N[2-(dimethylamino)ethyl]carbamoyl}methyl methyl(2E)but-2ene-1,4    dioate;-   methyl 2-(4-methylpiperazinyl)-2-oxoethyl(2E)but-2-ene-1,4-dioate;-   methyl    {N-[(propylamino)carbonyl]carbamoyl}methyl(2E)but-2ene-1,4-dioate;-   2-(4-acetylpiperazinyl)-2-oxoethyl methyl(2E)but-2ene-1,4-dioate;-   {N,N-bis[2-(methylethoxy)ethyl]carbamoyl}methyl    methyl(2E)but-2-ene-1,4-dioate;-   methyl 2-(4-benzylpiperazinyl)-2-oxoethyl(2E)but-2-ene-1,4-dioate;-   [N,N-bis(2-ethoxyethyl)carbamoyl]methyl    methyl(2E)but-2-ene-1,4-dioate;-   2-{ (2 S)-2-[(tert-butyl)oxycarbonyl]pyrrolidinyl}-2-oxoethyl    methyl(2E)but-2ene- 1,4-dioate;-   1-{2-{(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetyl}(2S)pyrrolidine-2-carboxylic    acid;-   (N-{[(tert-butyl)oxycarbonyl]methyl}-N-methylcarbamoyl)methyl    methyl(2E)but-2ene 1,4-dioate;    {N-(ethoxycarbonyl)methyl]-N-methylcarbamoyl}methyl    methyl(2E)but-2-ene-1,4-dioate;-   methyl 1-methyl-2-morpholin-4-yl-2-oxoethyl(2E)but-2-ene-1,4-dioate;    [N,N-bis(2-methoxyethyl)carbamoyl]ethyl    methyl(2E)but-2-ene-1,4-dioate;-   (N,N-dimethylcarbamoyl)ethyl methyl(2E)but-2-ene-1,4-dioate;-   2-{2-[(2E)-3-(methoxy    carbonyl)prop-2-enoyloxyl]-N-methylacetylamino}acetic acid;-   (N-{ [(tert-butyl)oxycarbonyl]methyl}carbamoyl)methyl    methyl(2E)but-2-ene- 1,4-dioate;-   (2E)but-methyl-N-{[(methylethyl)oxycarbonyl]methyl}carbamoyl)methyl(2E)but-2-ene-    1,4-dioate; {N-[(ethoxycarbonyl)methyl]-N-benzylcarbamoyl}methyl    methyl(2E)but-2-ene-1,4-dioate;-   {N-[(ethoxycarbonyl)methyl]-N-benzylcarbamoyl}ethyl    methyl(2E)but-2-ene-1,4-dioate;-   {N-[(ethoxycarbonyl)methyl]-N-methylcarbamoyl }ethyl    methyl(2E)but-2-ene- 1,4-dioate;-   (1S)-1-methyl-2-morpholin-4-yl-2-oxo ethyl    methyl(2E)but-2-ene-1,4-dioate;-   (1S)-1-[N,N-bis(2-methoxyethyl)carbamoyl]ethyl    methyl(2E)but-2-ene-1,4-dioate;-   (1R)-1-(N,N-diethylcarbamoyl)ethyl methyl(2E)but-2-ene-1,4-dioate;    or-   (1S)-1-(N,N-diethylcarbamoyl)ethyl methyl(2E)but-2-ene-1,4-dioate;    or a pharmaceutically acceptable salt, clathrate, solvate, tautomer,    or stereoisomer thereof.

In certain embodiments of a compound of Formula (III), the compound is:

or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer thereof

In certain embodiments of a compound of Formula (III), the compound is:

-   (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate;-   methyl[N-benzylcarbamoyl]methyl(2E)but-2-ene-1,4-dioate; methyl    2-morpholin-4-yl-2-oxoethyl(2E)but-2-ene-1,4-dioate;-   (N-butylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate;-   [N-(2-methoxyethyl)carbamoyl]methyl methyl(2E)but-2-ene-1,4-dioate;-   2-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}acetic    acid;-   {2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}butanoic    acid;-   methyl(N-(1,3,4-thiadiazol-2-yl)carbamoyl)methyl(2E)but-2ene-1,4-dioate;-   (N,N-dimethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate;-   (N-methoxy-N-methylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate;-   bis-(2-methoxyethylamino)carbamoyl]methyl    methyl(2E)but-2-ene-1,4-dioate;-   [N-(methoxycarbonyl)carbamoyl]methyl methyl(2E)but-2ene-1,4-dioate;-   methyl 2-oxo-2-piperazinylethyl(2E)but-2-ene-1,4-dioate;-   methyl    2-oxo-2-(2-oxo(1,3-oxazolidin-3-yl)ethyl(2E)but-2ene-1,4-dioate;-   {N[2-(dimethylamino)ethyl]carbamoyl }methyl    methyl(2E)but-2ene-1,4-dioate;-   (N-[(methoxycarbonyl)ethyl]carbamoyl)methyl    methyl(2E)but-2-ene-1,4-dioate; or-   2-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}propanoic    acid; or a-   pharmaceutically acceptable salt, clathrate, solvate, tautomer, or    stereoisomer thereof

In certain embodiments of a compound of Formula (III), the compound is:

or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer thereof.

In certain embodiments of a compound of Formula (III), the compound is:

or a clathrate or solvate thereof. In a particular embodiment,

may be administered as a cocrystal in the methods provided herein. Incertain embodiments, the cocrystals are cocrystals with urea, fumaricacid, succinic acid, maleic acid, malic acid, or citric acid or thosedisclosed in US patent application publication number US 2014-0179778A1.

In certain embodiments of a compound of Formula (III), the compound is:

or a clathrate or solvate thereof.

In certain embodiments of a compound of Formula (III), the compound is:

or a clathrate or solvate thereof.

In certain embodiments of a compound of Formula (III), the compound is:

or a clathrate or solvate thereof.

The compounds recited in paragraphs [00261] and [00263] are named usingChemistry 4-D Draw Pro, Version 7.01c (ChemInnovation Software, Inc.,San Diego, Calif.).

In one embodiment, the compounds of Formula (III) may be prepared usingmethods known to those skilled in the art, for example, as disclosed inU.S. Pat. No. 8,148,414 B2.

In one embodiment, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in WO2013/119677, such as the compounds of Formula (IV):

-   -   or a pharmaceutically acceptable salt, clathrate, solvate,        tautomer, or stereoisomer thereof, wherein    -   R⁹ is C₁₋₆ alkyl;    -   R¹⁰ and R¹¹ are each independently hydrogen, C₁₋₆ alkyl, or        substituted C₁₋₆ alkyl; and    -   R¹² is C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₁₋₆ alkenyl,        substituted C₁₋₆ alkenyl, C₁₋₆ heteroalkyl, substituted C₁₋₆        heteroalkyl, C₃₋₈ cycloalkyl, substituted C₃₋₈ cycloalkyl, C₆₋₈        aryl, substituted C₆₋₈ aryl, or    -   —OR¹³ wherein R¹³ is C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₃₋₁₀        cycloalkyl, substituted C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, or        substituted C₆₋₁₀ aryl;    -   wherein each substituent is independently halogen, —OH, —CN,        —CF₃, ═O, —NO₂, benzyl, —C(O)NR¹⁴ ₂, —R¹⁴, —OR¹⁴, —C(O)R¹³, or        —NR¹⁴ ₂ wherein each R¹⁴ is independently hydrogen or C₁₋₄        alkyl.

In certain embodiments of a compound of Formula (IV), each substituentis independently halogen, —OH, —CN, —CF₃, —R¹⁴, —OR¹⁴ ₂ wherein each R¹⁴is independently hydrogen or C₁₋₄ alkyl.

In certain embodiments of a compound of Formula (IV), each substituentis independently ═O, C₁₋₄ alkyl, and —COOR¹⁴ wherein R¹⁴ is hydrogen orC₁₋₄ alkyl.

In certain embodiments of a compound of Formula (IV), R⁹ is C₁₋₆ alkyl;in certain embodiments, R⁹ is C₁₋₃ alkyl; and in certain embodiments, R⁹is methyl or ethyl.

In certain embodiments of a compound of Formula (IV), R⁹ is methyl.

In certain embodiments of a compound of Formula (IV), R⁹ is ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

In certain embodiments of a compound of Formula (IV), R⁹ is methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

In certain embodiments of a compound of Formula (IV), one of R¹⁰ and R¹¹is hydrogen and the other of R¹⁰ and R¹¹ is C₁₋₆ alkyl. In certainembodiments of a compound of Formula (IV), one of R¹⁰ and R¹¹ ishydrogen and the other of R¹⁰ and R¹¹ is C₁₋₄ alkyl.

In certain embodiments of a compound of Formula (IV), one of R¹⁰ and R¹¹is hydrogen and the other of R¹⁰ and R¹¹ is methyl, ethyl, n-propyl, orisopropyl. In certain embodiments of a compound of Formula (IV), each ofR¹⁰ and R¹¹ is hydrogen.

In certain embodiments of a compound of Formula (IV), R¹² is C₁₋₆ alkyl;one of R¹⁰ and R¹¹ is hydrogen and the other of R¹⁰ and R¹¹ is C₁₋₆alkyl; and R⁹ is C₁₋₆ alkyl.

In certain embodiments of a compound of Formula (IV), R¹² is —OR¹³.

In certain embodiments of a compound of Formula (IV), R¹³ is C₁₋₄ alkyl,cyclohexyl, or phenyl.

In certain embodiments of a compound of Formula (IV), R¹² is methyl,ethyl, n-propyl, or isopropyl; one of R¹⁰ and R¹¹ is hydrogen and theother of R¹⁰ and R¹¹ is methyl, ethyl, n-propyl, or isopropyl.

In certain embodiments of a compound of Formula (IV), R¹² is substitutedC₁₋₂ alkyl, wherein each substituent is independently —COOH,—NHC(O)CH₂NH₂, or —NH₂.

In certain embodiments of a compound of Formula (IV), R¹² is ethoxy,methylethoxy, isopropyl, phenyl, cyclohexyl, cyclohexyloxy,—CH(NH₂)CH₂COOH, —CH₂CH(NH₂)COOH, —CH(NHC(O)CH₂NH₂)—CH₂COOH, or—CH₂CH(NHC(O)CH₂NH₂)—COOH.

In certain embodiments of a compound of Formula (IV), R⁹ is methyl orethyl; one of R¹⁰ and R¹¹ is hydrogen and the other of R¹⁰ and R¹¹ ishydrogen, methyl, ethyl, n-propyl, or isopropyl; and R¹² is C₁₋₃ alkyl,substituted C₁₋₂ alkyl wherein each substituent group is —COOH,—NHC(O)CH₂NH₂, —NH₂, or —OR¹³ wherein R¹³ is C₁₋₃ alkyl, cyclohexyl,phenyl, or cyclohexyl.

In certain embodiments of a compound of Formula (IV), the compound is:ethoxycarbonyloxyethyl methyl(2E)but-2-ene-1,4-dioate;methyl(methylethoxycarbonyloxy)ethyl(2E)but-2-ene-1,4-dioate; or(cyclohexyloxycarbonyloxy)ethyl methyl(2E)but-2-ene-1,4-dioate; or aclathrate, solvate, or stereoisomer thereof.

In certain embodiments of a compound of Formula (IV), the compound is:

or a clathrate, solvate, or stereoisomer thereof.

In certain embodiments of a compound of Formula (IV), the compound is:methyl(2-methylpropanoyloxy)ethyl(2E)but-2-ene-1,4-dioate; methylphenylcarbonyloxyethyl(2E)but-2-ene-1,4-dioate;cyclohexylcarbonyloxybutyl methyl(2E)but-2-ene-1,4-dioate;[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]ethylmethyl(2E)but-2-ene-1,4-dioate; or methyl2-methyl-1-phenylcarbonyloxypropyl(2E)but-2-ene-1,4-dioate; or aclathrate, solvate, or stereoisomer thereof.

In certain embodiments of a compound of Formula (IV), the compound is:

or a clathrate, solvate, or stereoisomer thereof.

In certain embodiments of a compound of Formula (IV), the compound is:

-   ethoxycarbonyloxyethyl methyl(2E)but-2-ene-1,4-dioate;-   methyl(methylethoxycarbonyloxy)ethyl(2E)but-2-ene-1,4-dioate;-   methyl(2-methylpropanoyloxy)ethyl(2E)but-2-ene-1,4-dioate;-   methyl phenylcarbonyloxyethyl(2E)but-2-ene-1,4-dioate;-   cyclohexylcarbonyloxybutyl methyl(2E)but-2-ene-1,4-dioate;-   [(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]ethyl    methyl(2E)but-2-ene-1,4-dioate;-   (cyclohexyloxycarbonyloxy)ethyl methyl(2E)but-2-ene-1,4-dioate;-   methyl 2-methyl-l-phenylcarbonyloxypropyl(2E)but-2-ene-1,4-dioate;    or a clathrate, solvate, or stereoisomer thereof.

In certain embodiments of a compound of Formula (IV), the compound is:

-   3-({[(2E)-3    -(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(3S)-3    -aminopropanoic acid, 2,2,2-trifluoroacetic acid;-   3-({[(2E)-3    -(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(2S)-2-aminopropanoic    acid, 2,2,2-trifluoroacetic acid;-   3-({[(2E)-3    -(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(3S)-3    -(2-aminoacetylamino)propanoic acid, 2,2,2-trifluoroacetic acid; or-   3-{[(2E)-3    -(methoxycarbonyl)prop-2enoyloxy]ethoxycarbonyloxy}(2S)-2-aminopropanoic    acid, chloride; or a clathrate, solvate, or stereoisomer thereof.

In certain embodiments of a compound of Formula (IV), the compound is:

or a clathrate, solvate, or stereoisomer thereof.

In certain embodiments of a compound of Formula (IV), the compound is:

or a pharmaceutically acceptable salt, clathrate, solvate, orstereoisomer thereof.

In certain embodiments of a compound of Formula (IV), the compound is:

or a clathrate, solvate, or stereoisomer thereof.

The compounds recited in paragraphs [00287], [00289], [00291], and[00292] are named using Chemistry 4-D Draw Pro, Version 7.01c(ChemInnovation Software, Inc., San Diego, Calif.).

In one embodiment, the compounds of Formula (IV) may be prepared usingmethods known to those skilled in the art, for example, as disclosed inU.S. Pat. No. 8,148,414 B2.

In one embodiment, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in U.S. Patent Application Publication No. 2014/0057918, suchas the compounds of Formula (V):

-   -   or a pharmaceutically acceptable salt, clathrate, or solvate        thereof, wherein    -   R¹⁵ is C₁₋₆ alkyl; and    -   m is an integer from 2 to 6.

In certain embodiments of a compound of Formula (V), R¹⁵ is methyl.

In certain embodiments of a compound of Formula (V), R¹⁵ is ethyl.

In certain embodiments of a compound of Formula (V), R¹⁵ is C₃₋₆ alkyl.

In certain embodiments of a compound of Formula (V), R¹⁵ is methyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

In certain embodiments of a compound of Formula (V), R¹⁵ is methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

In certain embodiments of a compound of Formula (V), the compound is:

-   methyl (2-morpholinoethyl)fumarate;-   methyl (3-morpholinopropyl)fumarate;-   methyl (4-morpholinobutyl)fumarate;-   methyl (5-morpholinopentyl)fumarate; or-   methyl (6-morpholinohexyl)fumarate;-   or a pharmaceutically acceptable salt, clathrate, or solvate    thereof.

In certain embodiments of a compound of Formula (V), the compound is:

or a pharmaceutically acceptable salt, clathrate, or solvate thereof.

The compounds recited in paragraph [00304] are named using Chemistry 4-DDraw Pro, Version 7.01c (ChemInnovation Software, Inc., San Diego,Calif.).

In one embodiment, the compounds of Formula (V) may be prepared usingmethods known to those skilled in the art, for example, as disclosed inU.S. Patent Application Publication No. 2014/0057918.

In one embodiment, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in WO2013/119677, such as the compounds of Formula (VI):

or a pharmaceutically acceptable salt, clathrate, solvate, orstereoisomer thereof, wherein:

-   -   R¹⁶ is C₁₋₁₀ alkyl, C₅₋₁₄ aryl, hydroxyl, —O—C₁₋₁₀ alkyl, or        —O—C₅₋₁₄ aryl;    -   each of R¹⁷, R¹⁸, and R¹⁹ independently is C₁₋₁₀ alkyl, C₅₋₁₄        aryl, hydroxyl, —O—C₁₋₁₀ alkyl, —O—C₅₋₁₄ aryl, or

-   -   wherein R²⁰ is C₁₋₆ alkyl; each of which can be optionally        substituted; and each of n, p, and q independently is 0-4;    -   provided that at least one of R¹⁷, R¹⁸, and R¹⁹ is

In certain embodiments of a compound of Formula (VI), R²⁰ is optionallysubstituted C₁₋₆ alkyl. In certain embodiments of a compound of Formula(VI), R² is optionally substituted methyl, ethyl, or isopropyl. Incertain embodiments of a compound of Formula (VI), R²⁰ is methyl.

In certain embodiments of a compound of Formula (VI), R¹⁶ is C₁₋₁₀alkyl. In certain embodiments of a compound of Formula (VI), R¹⁶ isoptionally substituted C₁₋₆ alkyl. In certain embodiments of a compoundof Formula (VI), R¹⁶ is optionally substituted methyl, ethyl, orisopropyl. In certain embodiments of a compound of Formula (VI), R¹⁶ isoptionally substituted C₅₋₁₅ aryl. In certain embodiments of a compoundof Formula (VI), R¹⁶ is optionally substituted C₅-C₁₀ aryl.

In one embodiment, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in WO2013/119677, such as the compounds of Formula (VI'):

-   -   or a pharmaceutically acceptable salt, clathrate, solvate, or        stereoisomer thereof, wherein    -   R¹⁶ is C₁₋₁₀ alkyl, C₆₋₁₀ aryl, hydroxyl, alkyl, or —O—C₆₋₁₀        aryl;    -   each of R¹⁷, R¹⁸, and R¹⁹ independently is C₁₋₁₀ alkyl, C₆₋₁₀        aryl, hydroxyl, alkyl, —O—C₆₋₁₀ aryl, or

-   -   wherein R²⁰ is C₁₋₆ alkyl; each of which can be optionally        substituted; and    -   each of n, p, and q independently is 0-4;    -   provided that at least one of R¹⁷, R¹⁸, and R¹⁹ is

In certain embodiments of a compound of Formula (VI′), R²⁰ is methyl.

In certain embodiments of a compound of Formula (VI) or Formula (VI′),the compound is: (dimethylsilanediyl)dimethyl difumarate; methyl((trimethoxysilyl)methyl) fumarate; methyl ((trihydroxysilyl)methyl)fumarate; or trimethyl (methylsilanetriyl) trifumarate; or apharmaceutically acceptable salt thereof.

In certain embodiments of a compound of Formula (VI) or Formula (VI′),the compound is:

or a pharmaceutically acceptable salt thereof.

In one embodiment, the compounds of Formula (VI) and Formula (VI′) maybe prepared using methods known to those skilled in the art, forexample, as disclosed in WO2013/119677.

In one embodiment, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in WO2013/119677, such as the compounds of Formula (VII):

-   -   or a pharmaceutically acceptable salt, clathrate, solvate, or        stereoisomer thereof, wherein:    -   wherein R²¹ is C₁₋₆ alkyl; and    -   each of R²² and R²³ independently is C₁₋₁₀ alkyl or C₅₋₁₄ aryl;    -   each of which can be optionally substituted.

In certain embodiments of a compound of Formula (VII), R²¹ is optionallysubstituted C₁₋₆ alkyl. In certain embodiments of a compound of Formula(VII), R²¹ is optionally substituted methyl, ethyl, or isopropyl. Incertain embodiments of a compound of Formula (VII), R²¹ is methyl.

In certain embodiments of a compound of Formula (VII), each of R²² andR²³ independently is optionally substituted C₁₋₁₀ alkyl. In certainembodiments of a compound of Formula (VII), each of R²² and R²³independently is optionally substituted C₁₋₆ alkyl. In certainembodiments of a compound of Formula (VII), each of R²² and R²³independently is optionally substituted methyl, ethyl, or isopropyl. Incertain embodiments of a compound of Formula (VII), each of R²² and R²³independently is optionally substituted C₅₋₁₄ aryl. In certainembodiments of a compound of Formula (VII), each of R²² and R²³independently is optionally substituted C₅₋₁₀ aryl.

In one embodiment, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in WO2013/119677, such as the compounds of Formula (VII′):

-   -   or a pharmaceutically acceptable salt, clathrate, solvate, or        stereoisomer thereof, wherein    -   is C₁₋₆ alkyl; and    -   each of R²² and R²³ independently is C₁₋₁₀ alkyl or C₆₋₁₀ aryl.

In one embodiment, the compounds of Formula (VII) and Formula (VII′) maybe prepared using methods known to those skilled in the art, forexample, as disclosed in WO2013/119677.

In one embodiment, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in WO2013/119677, such as the compounds of Formula (VIII):

-   -   or a pharmaceutically acceptable salt, clathrate, solvate, or        stereoisomer thereof, wherein:    -   R²⁴ is C₁₋₆ alkyl;    -   each of R²⁵, R²⁶, and R²⁷ independently is hydroxyl, C₁₋₁₀        alkyl, C₅₋₁₄ aryl, —O—C₁₋₁₀ alkyl, or —O—C₅₋₁₄ aryl;    -   each of which can be optionally substituted; and    -   s is 1 or 2.

In certain embodiments of a compound of Formula (VIII), R²⁴ isoptionally substituted C₁-C₆ alkyl. In certain embodiments of a compoundof Formula (VIII), R²⁴ is optionally substituted methyl, ethyl, orisopropyl. In certain embodiments of a compound of Formula (VIII), R²⁴is methyl.

In certain embodiments of a compound of Formula (VIII), each of R²⁵,R²⁶, and R²⁷ is hydroxyl. In certain embodiments of a compound ofFormula (VIII), each of R²⁵, R²⁶, and R²⁷ independently is optionallysubstituted C₁₋₁₀ alkyl. In certain embodiments of a compound of Formula(VIII), each of R²⁵, R²⁶, and R²⁷ independently is optionallysubstituted C₁₋₆ alkyl. In certain embodiments of a compound of Formula(VIII), each of R²⁵, R²⁶, and R²⁷ independently is optionallysubstituted methyl, ethyl, or isopropyl. In certain embodiments of acompound of Formula (VIII), each of R²⁵, R²⁶, and R²⁷ independently isoptionally substituted C₅₋₁₄ aryl. In certain embodiments of a compoundof Formula (VIII), each of R²⁵, R²⁶, and R²⁷ independently is optionallysubstituted C₅₋₁₀ aryl.

In one embodiment, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in WO2013/119677, such as the compounds of Formula (VIII′):

-   -   or a pharmaceutically acceptable salt, clathrate, solvate, or        stereoisomer thereof, wherein:    -   R²⁴ is C₁₋₆ alkyl;    -   each of R²⁵, R²⁶, and R²⁷ independently is hydroxyl, C₁₋₁₀        alkyl, C₆₋₁₀ aryl, —O—C₁₋₁₀ alkyl, or —O—C₆₋₁₀ aryl; and s is 1        or 2.

In one embodiment, the compounds of Formula (VIII) and Formula (VIII′)may be prepared using methods known to those skilled in the art, forexample, as disclosed in WO2013/119677.

In one embodiment, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in WO2013/119677, such as the compounds of Formula (IX):

-   -   or a pharmaceutically acceptable salt, clathrate, solvate, or        stereoisomer thereof, wherein    -   each of R²⁸ independently is C₁₋₆ alkyl; and    -   R²⁹ is C₁₋₁₀ alkyl;    -   each of which can be optionally substituted.

In certain embodiments of a compound of Formula (IX), each of R²⁸independently is optionally substituted C₁₋₆ alkyl. In certainembodiments of a compound of Formula (IX), each of R²⁸ independently isoptionally substituted methyl, ethyl, or isopropyl. In certainembodiments of a compound of Formula (IX), each of R²⁸ is methyl.

In certain embodiments of a compound of Formula (IX), R²⁹ is optionallysubstituted C₁₋₆ alkyl. In certain embodiments of a compound of Formula(IX), R²⁹ is optionally substituted methyl, ethyl, or isopropyl.

In one embodiment, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in WO2013/119677, such as the compounds of Formula (IX′):

-   -   or a pharmaceutically acceptable salt, clathrate, solvate, or        stereoisomer thereof, wherein    -   R²⁸ is C₁₋₆ alkyl; and    -   R²⁹ is C₁₋₁₀ alkyl.

In one embodiment, the compounds of Formula (IX) and Formula (IX′) maybe prepared using methods known to those skilled in the art, forexample, as disclosed in WO2013/119677.

In one embodiment, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in U.S. Pat. No. 8,669,281 B1, such as the compounds ofFormula (X):

-   -   or a pharmaceutically acceptable salt, clathrate, solvate,        tautomer, or stereoisomer thereof, wherein    -   R³⁰ is unsubstituted C₁₋₆ alkyl;    -   L_(a) is substituted or unsubstituted C₁₋₆ alkyl linker,        substituted or unsubstituted C₃₋₁₀ carbocycle, substituted or        unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted        heterocycle comprising one or two 5- or 6-member rings and 1-4        heteroatoms selected from N, O, and S, or substituted or        unsubstituted heteroaryl comprising one or two 5- or 6-member        rings and 1-4 heteroatoms selected from N, O, and S; and    -   R³¹ and R³² are each, independently, hydrogen, substituted or        unsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆        alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted        or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted C₃₋₁₀        carbocycle, substituted or unsubstituted heterocycle comprising        one or two 5- or 6-member rings and 1-4 heteroatoms selected        from N, O, and S, or substituted or unsubstituted heteroaryl        comprising one or two 5- or 6-member rings and 1-4 heteroatoms        selected from N, O, and S;    -   or alternatively, R₃₁ and R³², together with the nitrogen atom        to which they are attached, form a substituted or unsubstituted        heteroaryl comprising one or two 5- or 6-member rings and 1-4        heteroatoms selected from N, O, and S or a substituted or        unsubstituted heterocycle comprising one or two 5- or 6-member        rings and 1-4 heteroatoms selected from N, O, and S.

In certain embodiments of a compound of Formula (X), R³⁰ is methyl. Incertain embodiments of a compound of Formula (X), R³⁰ is ethyl.

In certain embodiments of a compound of Formula (X), L_(a) issubstituted or unsubstituted C₁₋₆ alkyl linker. In certain embodimentsof a compound of Formula (X), L_(a) is substituted or unsubstituted C₁₋₃alkyl linker. In certain embodiments of a compound of Formula (X), L_(a)is substituted or unsubstituted C₂ alkyl linker. In certain embodimentsof a compound of Formula (X), L_(a) is a methyl substituted orunsubstituted C₂ alkyl linker. In certain embodiments of a compound ofFormula (X), L_(a) is a di-methyl substituted or unsubstituted C₂ alkyllinker. In certain embodiments of a compound of Formula (X), L_(a) is amethyl or di-methyl substituted C₂ alkyl linker. In certain embodimentsof a compound of Formula (X), L_(a) is unsubstituted C₂ alkyl linker.

In certain embodiments of a compound of Formula (X), R³¹ is substitutedor unsubstituted C₁₋₆ alkyl. In certain embodiments of a compound ofFormula (X), R³¹ is unsubstituted C₁₋₆ alkyl. In certain embodiments ofa compound of Formula (X), R³¹ is unsubstituted C₁₋₃ alkyl. In certainembodiments of a compound of Formula (X), R³¹ is unsubstituted C₁₋₂alkyl.

In certain embodiments of a compound of Formula (X), R³¹ isC(O)OR_(a)-substituted C₁₋₆ alkyl, wherein R_(a) is hydrogen orunsubstituted C₁₋₆ alkyl. In certain embodiments of a compound ofFormula (X), R³¹ is S(O)(O)R_(b)-substituted C₁₋₆ alkyl, wherein R_(b)is unsubstituted C₁₋₆ alkyl.

In certain embodiments of a compound of Formula (X), R³² is hydrogen. Incertain embodiments of a compound of Formula (X), R³² is substituted orunsubstituted C₁₋₆ alkyl. In certain embodiments of a compound ofFormula (X), R³² is unsubstituted C₁₋₆ alkyl.

In certain embodiments of a compound of Formula (X), R³¹ and R³²,together with the nitrogen atom to which they are attached, form asubstituted or unsubstituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O, and S, or asubstituted or unsubstituted heterocycle comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O, and S.

In certain embodiments of a compound of Formula (X), R³¹ and R³²,together with the nitrogen atom to which they are attached, form asubstituted or unsubstituted heterocycle comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O, and S.

In certain embodiments of a compound of Formula (X), R³¹ and R³²,together with the nitrogen atom to which they are attached, form asubstituted or unsubstituted pyrrolidinyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl,tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl ring.

In certain embodiments of a compound of Formula (X), R³¹ and R³²,together with the nitrogen atom to which they are attached, form asubstituted or unsubstituted piperidinyl ring.

In certain embodiments of a compound of Formula (X), R³¹ and R³²,together with the nitrogen atom to which they are attached, form anunsubstituted piperidinyl ring.

In certain embodiments of a compound of Formula (X), R³¹ and R³²,together with the nitrogen atom to which they are attached, form ahalogen substituted piperidinyl ring. In certain embodiments of acompound of Formula (X), R³¹ and R³², together with the nitrogen atom towhich they are attached, form a 4-halogen substituted piperidinyl ring.

In certain embodiments of a compound of Formula (X), R³¹ and R³²,together with the nitrogen atom to which they are attached, form anunsubstituted morpholinyl ring.

In certain embodiments of a compound of Formula (X), R³¹ and R³²,together with the nitrogen atom to which they are attached, form anunsubstituted pyrrolidinyl ring.

In certain embodiments of a compound of Formula (X), R³¹ and R³²,together with the nitrogen atom to which they are attached, form asubstituted or unsubstituted heteroaryl comprising one or two 5 or6-member rings and 1-4 heteroatoms selected from N, O, and S.

In certain embodiments of a compound of Formula (X), R³¹ is substitutedor unsubstituted C₆₋₁₀ aryl. In certain embodiments of a compound ofFormula (X), R³¹ is unsubstituted C₆-C₁₀ aryl. In certain embodiments ofa compound of Formula (X), R³¹ is unsubstituted phenyl. In certainembodiments of a compound of Formula (X), R³¹ is unsubstituted benzyl.

In one embodiment, the compounds of Formula (X) may be prepared usingmethods known to those skilled in the art, for example, as disclosed inU.S. Pat. No. 8,669,281 B1.

In one embodiment, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in U.S. Pat. No. 8,669,281 B 1, such as the compounds ofFormula (X′):

-   -   or a pharmaceutically acceptable salt, clathrate, solvate,        tautomer, or stereoisomer thereof, wherein    -   R³³ is unsubstituted C₁₋₆ alkyl;    -   L_(a′) is substituted or unsubstituted C₁₋₆ alkyl linker,        substituted or unsubstituted C₃₋₁₀ carbocycle, substituted or        unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted        heterocycle comprising one or two 5- or 6-member rings and 1-4        heteroatoms selected from N, O, and S, or substituted or        unsubstituted heteroaryl comprising one or two 5- or 6-member        rings and 1-4 heteroatoms selected from N, O, and S; and    -   R³⁴ is hydrogen, substituted or unsubstituted C₁₋₆ alkyl,        substituted or unsubstituted C₂₋₆ alkenyl, substituted or        unsubstituted C₂₋₆ alkynyl, substituted or unsubstituted C₆₋₁₀        aryl, substituted or unsubstituted C₃₋₁₀ carbocycle, substituted        or unsubstituted heterocycle comprising one or two 5- or        6-member rings and 1-4 heteroatoms selected from N, O, and S, or        substituted or unsubstituted heteroaryl comprising one or two 5-        or 6-member rings and 1-4 heteroatoms selected from N, O, and S.

In certain embodiments of a compound of Formula (X′), R³³ is methyl. Incertain embodiments of a compound of Formula (X′), R³³ is ethyl.

In certain embodiments of a compound of Formula (X′), L_(a′) issubstituted or unsubstituted C₁₋₆ alkyl linker. In certain embodimentsof a compound of Formula (X′), L_(a′) is substituted or unsubstitutedC₁₋₃ alkyl linker.

In certain embodiments of a compound of Formula (X′), L_(a′)issubstituted or unsubstituted C₂ alkyl linker. In certain embodiments ofa compound of Formula (X′), L_(a′) is methyl substituted orunsubstituted C₂ alkyl linker. In certain embodiments of a compound ofFormula (X′), L_(a′) is di-methyl substituted or unsubstituted C₂ alkyllinker. In certain embodiments of a compound of Formula (X′), L_(a′) ismethyl or di-methyl substituted C₂ alkyl linker. In certain embodimentsof a compound of Formula (X′), L_(a′) is unsubstituted C₂ alkyl linker.

In certain embodiments of a compound of Formula (X′), R³⁴ is substitutedor unsubstituted C₁₋₆ alkyl. In certain embodiments of a compound ofFormula (X′), R³⁴ is unsubstituted C₁₋₆ alkyl. In certain embodiments ofa compound of Formula (X′), R³⁴ is methyl. In certain embodiments of acompound of Formula (X′), R³⁴ is unsubstituted C₁₋₃ alkyl. In certainembodiments of a compound of Formula (X′), R³⁴ is unsubstituted C₁-₂alkyl.

In certain embodiments of a compound of Formula (X′), R³⁴ isC(O)OR_(a′)-substituted C₁₋₆ alkyl, wherein R_(a′) is H or unsubstitutedC₁₋₆ alkyl. In certain embodiments of a compound of Formula (X′), R³⁴ isS(O)(O)R_(b′)-substituted C₁₋₆ alkyl, wherein R_(b) is unsubstitutedC₁₋₆ alkyl.

In one embodiment, the compounds of Formula (X′) may be prepared usingmethods known to those skilled in the art, for example, as disclosed inU.S. Pat. No. 8,669,281 B1.

In one embodiment, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in U.S. Pat. No. 8,669,281 B 1, such as the compounds ofFormula (X″):

-   -   or a clathrate, solvate, tautomer, or stereoisomer thereof,        wherein    -   A⁻is a pharmaceutically acceptable anion;    -   R³⁵ is unsubstituted C₁₋₆ alkyl;    -   L_(a″) is substituted or unsubstituted C₁₋₆ alkyl linker,        substituted or unsubstituted C₃₋₁₀ carbocycle, substituted or        unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted        heterocycle comprising one or two 5- or 6-member rings and 1-4        heteroatoms selected from N, O, and S, or substituted or        unsubstituted heteroaryl comprising one or two 5- or 6-member        rings and 1-4 heteroatoms selected from N, O, and S;    -   R³⁶ and R³⁷ are each, independently, hydrogen, substituted or        unsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆        alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted        or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted C₃₋₁₀        carbocycle, substituted or unsubstituted heterocycle comprising        one or two 5- or 6-member rings and 1-4 heteroatoms selected        from N, O, and S, or substituted or unsubstituted heteroaryl        comprising one or two 5- or 6-member rings and 1-4 heteroatoms        selected from N, O, and S;    -   or alternatively, R³⁶ and R³⁷, together with the nitrogen atom        to which they are attached, form a substituted or unsubstituted        heteroaryl comprising one or two 5- or 6-member rings and 1-4        heteroatoms selected from N, O, and S, or a substituted or        unsubstituted heterocycle comprising one or two 5- or 6-member        rings and 1-4 heteroatoms selected from N, O, and S; and R³⁸ is        substituted or unsubstituted C₁₋₆ alkyl.

In certain embodiments of a compound of Formula (X″), R³⁵ is methyl. Incertain embodiments of a compound of Formula (X″), R³⁵ is ethyl.

In certain embodiments of a compound of Formula (X″), L_(a″) issubstituted or unsubstituted C₁₋₆ alkyl linker. In certain embodimentsof a compound of Formula (X″), L_(a″)is substituted or unsubstitutedC₁₋₃ alkyl linker.

In certain embodiments of a compound of Formula (X″), L_(a″) issubstituted or unsubstituted C₂ alkyl linker. In certain embodiments ofa compound of Formula (X″), L_(a″) is methyl substituted orunsubstituted C₂ alkyl linker. In certain embodiments of a compound ofFormula (X″), L_(a″) is di-methyl substituted or unsubstituted C₂ alkyllinker. In certain embodiments of a compound of Formula (X″), L_(a″) ismethyl or di-methyl substituted C₂ alkyl linker. In certain embodimentsof a compound of Formula (X″), L_(a″) is unsubstituted C₂ alkyl linker.

In certain embodiments of a compound of Formula (X″), R³⁶ is substitutedor unsubstituted C₁₋₆ alkyl. In certain embodiments of a compound ofFormula (X″), R³⁶ is unsubstituted C₁₋₆ alkyl. In certain embodiments ofa compound of Formula (X″), R³⁶ is unsubstituted C₁₋₃ alkyl. In certainembodiments of a compound of Formula (X″), R³⁶ is unsubstituted C₁₋₂alkyl.

In certain embodiments of a compound of Formula (X″), R³⁶ isC(O)OR_(a″)-substituted C₁₋₆ alkyl, wherein R_(a″) is hydrogen orunsubstituted C₁₋₆ alkyl. In certain embodiments of a compound ofFormula (X″), R³⁶ is S(O)(O)R_(b″)-substituted C₁₋₆ alkyl, whereinR_(b″) is unsubstituted C₁₋₆ alkyl.

In certain embodiments of a compound of Formula (X”), R³⁶ and R³⁷,together with the nitrogen atom to which they are attached, form asubstituted or unsubstituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O, and S, or asubstituted or unsubstituted heterocycle comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O, and S.

In certain embodiments of a compound of Formula (X″), R³⁶ and R³⁷,together with the nitrogen atom to which they are attached, form asubstituted or unsubstituted heterocycle comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O, and S.

In certain embodiments of a compound of Formula (X″), R³⁶ and R³⁷,together with the nitrogen atom to which they are attached, form asubstituted or unsubstituted pyrrolidinyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl,tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl ring.

In certain embodiments of a compound of Formula (X″), R³⁶ and R³⁷,together with the nitrogen atom to which they are attached, form asubstituted or unsubstituted piperidinyl ring. In certain embodiments ofa compound of Formula (X″), R³⁶ and R³⁷, together with the nitrogen atomto which they are attached, form an unsubstituted piperidinyl ring. Incertain embodiments of a compound of Formula (X″), R³⁶ and R³⁷, togetherwith the nitrogen atom to which they are attached, form a halogensubstituted piperidinyl ring. In certain embodiments of a compound ofFormula (X″), R³⁶ and R³⁷, together with the nitrogen atom to which theyare attached, form a 4-halogen substituted piperidinyl ring.

In certain embodiments of a compound of Formula (X″), R³⁶ and R³⁷,together with the nitrogen atom to which they are attached, form anunsubstituted morpholinyl ring.

In certain embodiments of a compound of Formula (X″), R³⁶ and R³⁷,together with the nitrogen atom to which they are attached, form anunsubstituted pyrrolidinyl ring.

In certain embodiments of a compound of Formula (X″), R³⁶ and R³⁷,together with the nitrogen atom to which they are attached, form asubstituted or unsubstituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O, and S.

In certain embodiments of a compound of Formula (X″), R³⁶ is substitutedor unsubstituted C₆₋₁₀ aryl. In certain embodiments of a compound ofFormula (X″), R³⁶ is unsubstituted C₆₋₁₀ aryl. In certain embodiments ofa compound of Formula (X″), R³⁶ is unsubstituted phenyl. In certainembodiments of a compound of Formula (X″), R³⁶ is unsubstituted benzyl.

In certain embodiments of a compound of Formula (X″), R³⁷ is hydrogen.

In certain embodiments of a compound of Formula (X″), R³⁷ is substitutedor unsubstituted C₁₋₆ alkyl. In certain embodiments of a compound ofFormula (X″), R³⁷ is unsubstituted C₁₋₆ alkyl.

In certain embodiments of a compound of Formula (X″), R³⁸ isunsubstituted C₁₋₆ alkyl. In certain embodiments of a compound ofFormula (X″), R³⁸ is unsubstituted C₁₋₃ alkyl. In certain embodiments ofa compound of Formula (X″), R³⁸ is methyl.

In one embodiment, the compounds of Formula (X″) may be prepared usingmethods known to those skilled in the art, for example, as disclosed inU.S. Pat. No. 8,669,281 B1.

In one embodiment, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in U.S. Pat. No. 8,669,281 B 1, such as the compounds ofFormula (XI):

-   -   or a pharmaceutically acceptable salt, clathrate, solvate,        tautomer, or stereoisomer thereof, wherein    -   R³⁹ is unsubstituted C₁₋₆ alkyl;    -   R⁴⁰ and R⁴¹ are each, independently, hydrogen, substituted or        unsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆        alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted        or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted C₃₋₁₀        carbocycle, substituted or unsubstituted heterocycle comprising        one or two 5- or 6-member rings and 1-4 heteroatoms selected        from N, O, and S, or substituted or unsubstituted heteroaryl        comprising one or two 5- or 6-member rings and 1-4 heteroatoms        selected from N, O, and S;    -   R⁴², R⁴³, R⁴⁴, and R⁴⁵ are each, independently, hydrogen,        substituted or unsubstituted    -   C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,        substituted or unsubstituted C₂₋₆ alkynyl or C(O)OR_(b); and        R_(b) is H or substituted or unsubstituted C₁-C₆ alkyl.

In certain embodiments of a compound of Formula (XI), R³⁹ is methyl. Incertain embodiments of a compound of Formula (XI), R³⁹ is ethyl.

In certain embodiments of a compound of Formula (XI), R⁴⁰ is substitutedor unsubstituted C₁₋₆ alkyl. In certain embodiments of a compound ofFormula (XI), R⁴⁰ is unsubstituted C₁₋₆ alkyl. In certain embodiments ofa compound of Formula (XI), R⁴⁰ is unsubstituted C₁₋₃ alkyl. In certainembodiments of a compound of Formula (XI), R⁴⁰ is unsubstituted C₁₋₂alkyl.

In certain embodiments of a compound of Formula (XI), R⁴⁰ isC(O)OR_(b)-substituted C₁₋₆ alkyl, wherein R_(b) is hydrogen orunsubstituted C₁₋₆ alkyl. In certain embodiments of a compound ofFormula (XI), R⁴⁰ is S(O)(O)R_(b)-substituted C₁₋₆ alkyl, wherein R_(b)is unsubstituted C₁₋₆ alkyl.

In certain embodiments of a compound of Formula (XI), R⁴⁰ is substitutedor unsubstituted C₆₋₁₀ aryl. In certain embodiments of a compound ofFormula (XI), R⁴⁰ is unsubstituted C₆₋₁₀ aryl. In certain embodiments ofa compound of Formula (XI), R⁴⁰ is unsubstituted phenyl. In certainembodiments of a compound of Formula (XI), R⁴⁰ is unsubstituted benzyl.

In certain embodiments of a compound of Formula (XI), R⁴¹ is hydrogen.

In certain embodiments of a compound of Formula (XI), R⁴¹ is substitutedor unsubstituted C₁₋₆ alkyl. In certain embodiments of a compound ofFormula (XI), R⁴¹ is unsubstituted C₁₋₆ alkyl.

In certain embodiments of a compound of Formula (XI), R⁴², R⁴³, R⁴⁴ andR⁴⁵ are each hydrogen.

In certain embodiments of a compound of Formula (XI), R⁴² is substitutedor unsubstituted C₁₋₆ alkyl and R⁴³, R⁴⁴, and R⁴⁵ are each hydrogen. Incertain embodiments of a compound of Formula (XI), R⁴² is unsubstitutedC₁₋₆ alkyl and R⁴³, R⁴⁴, and R⁴⁵ are each hydrogen.

In certain embodiments of a compound of Formula (XI), R⁴⁴ is substitutedor unsubstituted C₁₋₆ alkyl and R⁴², R⁴³, and R⁴⁵ are each hydrogen. Incertain embodiments of a compound of Formula (XI), R⁴⁴ is unsubstitutedC₁₋₆ alkyl and R⁴², R⁴³, and R⁴⁵ are each hydrogen.

In certain embodiments of a compound of Formula (XI), R⁴² and R⁴⁴ areeach, independently, substituted or unsubstituted C₁₋₆ alkyl and R⁴³ andR⁴⁵ are each hydrogen. In certain embodiments of a compound of Formula(XI), R⁴² and R⁴⁴ are each, independently, unsubstituted C₁₋₆ alkyl andR⁴³ and R⁴⁵ are each hydrogen.

In certain embodiments of a compound of Formula (XI), R⁴² and R⁴³ areeach, independently, substituted or unsubstituted C₁₋₆ alkyl and R⁴⁴ andR⁴⁵ are each hydrogen. In certain embodiments of a compound of Formula(XI), R⁴² and R⁴³ are each, independently, unsubstituted C₁₋₆ alkyl andR⁴⁴ and R⁴⁵ are each hydrogen.

In certain embodiments of a compound of Formula (XI), R⁴⁴ and R⁴⁵ areeach, independently, substituted or unsubstituted C₁₋₆ alkyl and R⁴² andR⁴³ are each hydrogen. In certain embodiments of a compound of Formula(XI), R⁴⁴ and R⁴⁵ are each, independently, unsubstituted C₁₋₆ alkyl andR⁴² and R⁴³ are each hydrogen.

In one embodiment, the compounds of Formula (XI) may be prepared usingmethods known to those skilled in the art, for example, as disclosed inU.S. Pat. No. 8,669,281 B1.

In one embodiment, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in U.S. Pat. No. 8,669,281 B 1, such as the compounds ofFormula (XII):

-   -   or a pharmaceutically acceptable salt, clathrate, solvate,        tautomer, or stereoisomer thereof, wherein

R⁴⁶ is unsubstituted C₁₋₆ alkyl;

-   -   X is N, O, S, or SO₂;    -   Z is C or N;    -   t is 0, 1, 2, or 3;    -   y is 1 or 2;    -   w is 0, 1, 2, or 3;    -   v is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;    -   R⁴⁷, R⁴⁸, R⁴⁹, and R⁵⁰ are each, independently, hydrogen,        substituted or unsubstituted C₁₋₆ alkyl, substituted or        unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆        alkynyl or C(O)OR⁵²; and    -   R⁵² is hydrogen or substituted or unsubstituted C₁₋₆ alkyl; and        each R⁵¹ is, independently, hydrogen, halogen, substituted or        unsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆        alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted        or unsubstituted C₃₋₁₀ carbocycle, substituted or unsubstituted        heterocycle comprising one or two 5- or 6-member rings and 1-4        heteroatoms selected from N, O, and S, or substituted or        unsubstituted heteroaryl comprising one or two 5- or 6-member        rings and 1-4 heteroatoms selected from N, O, and S;    -   or, alternatively, two R⁵¹'s attached to the same carbon atom,        together with the carbon atom to which they are attached, form a        carbonyl, substituted or unsubstituted C₃₋₁₀ carbocycle,        substituted or unsubstituted heterocycle comprising one or two        5- or 6-member rings and 1-4 heteroatoms selected from N, O, and        S, or substituted or unsubstituted heteroaryl comprising one or        two 5- or 6-member rings and 1-4 heteroatoms selected from N, O,        and S;    -   or, alternatively, two R⁵¹'s attached to different atoms,        together with the atoms to which they are attached, form a        substituted or unsubstituted C₃-C₁₀ carbocycle, substituted or        unsubstituted heterocycle comprising one or two 5- or 6-member        rings and 1-4 heteroatoms selected from N, O, and S, or        substituted or unsubstituted heteroaryl comprising one or two 5-        or 6-member rings and 1-4 heteroatoms selected from N, O, and S.

In certain embodiments of a compound of Formula (XII), R⁴⁶ is methyl. Incertain embodiments of a compound of Formula (XII), R⁴⁶ is ethyl.

In certain embodiments of a compound of Formula (XII),

In certain embodiments of a compound of Formula (XII),

In certain embodiments of a compound of Formula (XII),

In certain embodiments of a compound of Formula (XII),

In certain embodiments of a compound of Formula (XII), R⁴⁷ issubstituted or unsubstituted C₁₋₆ alkyl and R⁴⁸, R⁴⁹, and R⁵⁰ are eachhydrogen. In certain embodiments of a compound of Formula (XII), R⁴⁷ isunsubstituted C₁₋₆ alkyl and R⁴⁸, R⁴⁹, and R⁵⁰ are each hydrogen.

In certain embodiments of a compound of Formula (XII), R⁴⁹ issubstituted or unsubstituted C₁₋₆ alkyl and R⁴⁷, R⁴⁸, and R⁵⁰ are eachhydrogen. In certain embodiments of a compound of Formula (XII), R⁴⁹ isunsubstituted C₁₋₆ alkyl and R⁴⁷, R⁴⁸, and R⁵⁰ are each hydrogen.

In certain embodiments of a compound of Formula (XII), R⁴⁷ and R⁴⁹ areeach, independently, substituted or unsubstituted C₁₋₆ alkyl and R⁴⁸ andR⁴⁹ are each hydrogen. In certain embodiments of a compound of Formula(XII), R⁴⁷ and R⁴⁹ are each, independently, unsubstituted C₁₋₆ alkyl andR⁴⁸ and R⁵⁰ are each hydrogen.

In certain embodiments of a compound of Formula (XII), R⁴⁷ and R⁴⁸ areeach, independently, substituted or unsubstituted C₁₋₆ alkyl and R⁴⁹ andR⁵⁰ are each hydrogen. In certain embodiments of a compound of Formula(XII), R⁴⁷ and R⁴⁸ are each, independently, unsubstituted C₁₋₆ alkyl andR⁴⁹ and R⁵⁰ are each hydrogen.

In certain embodiments of a compound of Formula (XII), R⁴⁹ and R⁵⁰ areeach, independently, substituted or unsubstituted C₁₋₆ alkyl and R⁴⁷ andR⁴⁸ are each hydrogen. In certain embodiments of a compound of Formula(XII), R⁴⁹ and R⁵⁰ are each, independently, unsubstituted C₁₋₆ alkyl andR⁴⁷ and R⁴⁸ are each hydrogen.

In one embodiment, the compounds of Formula (XII) may be prepared usingmethods known to those skilled in the art, for example, as disclosed inU.S. Pat. No. 8,669,281 B1.

In certain embodiments of a compound of Formula (X), (X′), (X″), (XI),or (XII), the compound is:

In certain embodiments of a compound of (XII), the compound is

In one embodiment, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in WO2014/096425, such as the compounds of Formula (XIII):

-   -   or a pharmaceutically acceptable salt, clathrate, solvate, or        stereoisomer thereof, wherein    -   L is is an alkanediyl group with 1 to 6 carbon atoms;    -   A is SO, SO₂, or NR⁵³, and    -   R⁵³ is C₁₋₆ alkyl or C₃₋₆ cycloalkyl.

In certain embodiments of a compound of Formula (XIII), L is analkanediyl group with 2, 3 or 4 carbon atoms,or with 2 or 4 carbonatoms, or with 2 carbons atoms. In certain embodiments of a compound ofFormula (XIII), L is —CH₂CH₂—. In certain embodiments of a compound ofFormula (XIII), A is SO or SO₂. In certain embodiments of a compound ofFormula (XIII), R⁵³ is methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, pentyl, sec-pentyl, or hexyl. In certainembodiments of a compound of Formula (XIII), R⁵³ is cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments of acompound of Formula (XIII), R⁵³ is C₁₋₄ alkyl, C₃ or C₄ or C₅cycloalkyl. In certain embodiments of a compound of Formula (XIII), R⁵³is methyl or isopropyl.

In one embodiment, the compounds of Formula (XIII) may be prepared usingmethods known to those skilled in the art, for example, as disclosed inWO2014/096425.

In one embodiment, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in WO2014/096425, such as the compounds of Formula (XIV):

-   -   or a clathrate, or solvate thereof.

In one embodiment, the compounds of Formula (XIV) may be prepared usingmethods known to those skilled in the art, for example, as disclosed inWO2014/096425.

In one embodiment, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in WO2014/096425, such as the compounds of Formula (XV):

or a clathrate, or solvate thereof.

In one embodiment, the compounds of Formula (XV) may be prepared usingmethods known to those skilled in the art, for example, as disclosed inWO2014/096425.

In one embodiment, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in WO2014/096425, such as the compounds of Formula (XVI):

-   -   or a clathrate, solvate, or stereoisomer thereof, wherein    -   R⁵⁴ and R⁵⁵ are each, independently, hydrogen, C₁₋₆ alkyl, or        C₃₋₆ cycloalkyl; R⁵⁶ and R⁵⁷ are each, independently, hydrogen        or C₁₋₆ alkyl; and    -   c and d are each, independently, an integer from 0 to 3.

In certain embodiments of a compound of Formula (XVI), R⁵⁴ and R⁵⁵ areeach, independently, hydrogen, methyl, or ethyl. In certain embodimentsof a compound of Formula (XVI), R⁵⁴ and R⁵⁵ are each, independently,hydrogen or methyl. In certain embodiments of a compound of Formula(XVI), R⁵⁴ and R⁵⁵ are both hydrogen; or R⁵⁴ is hydrogen and R⁵⁵ ismethyl. In certain embodiments of a compound of Formula (XVI), c and deach are, independently, 0 or 1. In certain embodiments of a compound ofFormula (XVI), c and d are both 0. In certain embodiments of a compoundof Formula (XVI), R⁵⁶ and R⁵⁷ are each, independently, C₁₋₅ alkyl orC₁₋₄ alkyl. In certain embodiments of a compound of Formula (XVI), R⁵⁶and R⁵⁷ are tert-butyl. In certain embodiments of a compound of Formula(XVI), R⁵⁶ and R⁵⁷ are identical.

In one embodiment, the compounds of Formula (XVI) may be prepared usingmethods known to those skilled in the art, for example, as disclosed inWO2014/096425.

In one embodiment, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in WO2014/096425, such as the compounds of Formula (XVII):

-   -   or a pharmaceutically acceptable salt, clathrate, solvate,        tautomer, or stereoisomer thereof, wherein    -   R⁵⁸, R⁵⁹, R⁶¹, and R⁶² are each, independently, hydrogen, C₁₋₆        alkyl, or C₃₋₆ cycloalkyl;    -   R⁶⁰ is hydrogen, C₃₋₆ cycloalkyl or C₁₋₆ alkyl, wherein the C₁₋₆        alkyl is optionally substituted with or more of amino,        NH—C(NH)NH₂, carboxamide, carboxylic acid, hydroxy, imidazole,        indole, mercapto, methylthio, phenyl, hydroxyphenyl, and wherein        one of R⁶¹ and R⁶² together with R⁶⁰ optionally belong to a 5 or        6-membered heteroaliphatic ring; and    -   f and g are each, independently, an integer from 0 to 3, with        the proviso that both f and g are not 0.

In certain embodiments of a compound of Formula (XVII), R⁶¹ and R⁶² areeach, independently, hydrogen or C₁₋₂ alkyl. In certain embodiments of acompound of Formula (XVII), R⁶¹ and R⁶² are hydrogen. In certainembodiments of a compound of Formula (XVII), R⁶¹ is hydrogen and R⁶² ismethyl. In certain embodiments of a compound of Formula (XVII), at leastone off and g is 0. In certain embodiments of a compound of Formula(XVII), g is 0.

In certain embodiments of a compound of Formula (XVII), R⁶⁰ is asubstituted C₁₋₆ alkyl, wherein the substituent is one or more of thefollowing: halogen, nitro, nitrile, urea, phenyl, aldehyde, sulfate,amino, NH—C(NH)NH₂, carboxamide, carboxylic acid, hydroxy, imidazole,indole, mercapto, methylthio, phenyl, and hydroxyphenyl. In particularembodiments the substituents are one or more of the following: amino,NH—C(NH)NH₂, carboxamide, carboxylic acid, hydroxy, imidazole, indole,mercapto, methylthio, phenyl, and hydroxyphenyl. In certain embodimentsof a compound of Formula (XVII), R⁶⁰ is —CH₂—C₆H₅. In certainembodiments of a compound of Formula (XVII), the compound is a compoundof Formula XVII′:

In one embodiment, the compounds of Formula (XVII) or (XVII′) may beprepared using methods known to those skilled in the art, for example,as disclosed in WO2014/096425.

In one embodiment, the prodrugs of monoalkyl fumarates are the prodrugsdisclosed in WO2014/096425, such as the compounds of Formula (XVIII):

-   -   or a pharmaceutically acceptable salt, clathrate, solvate, or        stereoisomer thereof, wherein    -   R⁶³ is hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl,        halogen, cyano, hydroxy, amino, carboxy, mercapto, 5 or        6-membered aryl or hetero aryl optionally substituted with one        of or more of methyl, tert-butyl, hydroxy, methoxy, halogen,        nitro, nitrile, amine, and carboxamide.

In certain embodiments of a compound of Formula (XVIII), R⁶³ ishydrogen, C₁₋₂ alkyl, halogen, cyano, amino, or hydroxy. In certainembodiments of a compound of Formula (XVIII), R⁶³ is hydrogen, hydroxyl,or methyl. In certain embodiments of a compound of Formula (XVIII), R⁶³is methyl.

In one embodiment, the compounds of Formula (XVIII) may be preparedusing methods known to those skilled in the art, for example, asdisclosed in WO2014/096425.

In certain embodiments of a compound of Formula (XIII), (XVI), (XVII),or (XVIII), the compound is:

5.1.3 Deuterated Fumarates

In one embodiment, the fumarates are isotopically enriched withdeuterium (²H).

In a particular embodiment, a deuterated fumarate is a compounddisclosed in U.S. patent application publication number US 2014-0179779A1, such as a compound of Formula

(XIX):

-   -   or a pharmaceutically acceptable salt, clathrate, solvate,        tautomer, or stereoisomer thereof, wherein    -   R⁶⁴ and R⁶⁷ are each independently hydrogen, deuterium,        deuterated methyl, deuterated ethyl, C₁₋₆ alkyl, phenyl, 3-7        membered saturated or partially unsaturated monocyclic        carbocyclic ring, 3-7 membered saturated or partially        unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, and sulfur, or a        5-6 membered heteroaryl ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, and sulfur; and    -   R⁶⁵ and R⁶⁶ are each independently hydrogen or deuterium,        provided that the compound of Formula (XIX) contains at least        one deuterium atom and that R⁶⁴ and R⁶⁷ are not hydrogen or        deuterium at the same time.

In particular, fumarate Isotopologues are the compounds disclosed in USpatent application publication number US 2014-0179779 A1, such as thecompounds of Formula (XIX'):

-   -   or a pharmaceutically acceptable salt, clathrate, solvate, or        stereoisomer thereof, wherein    -   R⁶⁴ and R⁶⁷ are each independently hydrogen, deuterium,        deuterated methyl, deuterated ethyl, or C₁₋₆ aliphatic, and    -   R⁶⁵ and R⁶⁶ are each independently hydrogen or deuterium,        provided that the compound of formula (XIX′) contains at least        one deuterium atom and that R⁶⁴ and R⁶⁷ are not hydrogen or        deuterium at the same time.

In certain embodiments of a compound of Formula (XIX) or Formula (XIX′),R⁶⁴ is hydrogen or —CH₃. In certain embodiments of a compound of Formula(XIX) or Formula (XIX′), R64 is —CD₃. In certain embodiments of acompound of Formula (XIX) or Formula (XIX′), R⁶⁴ is —CD₂CD₃.

In certain embodiments of a compound of Formula (XIX) or Formula (XIX′),R⁶⁷ is —CH₂D, —CHD₂, or —CD₃. In certain embodiments of a compound ofFormula (XIX) or Formula (XIX′), R⁶⁷ is H, —CH₃, —CH₂D, —CHD₂, or —CD₃.

In certain embodiments of a compound of Formula (XIX) or Formula (XIX′),R⁶⁴ is hydrogen or —CH₃ and R⁶⁷ is —CH₂D, —CHD₂, or —CD₃.

In certain embodiments of a compound of Formula (XIX) or Formula (XIX′),R⁶⁴ is —CD₃ and R⁶⁷ is —CH₂D, —CHD₂, or —CD₃.

In certain embodiments of a compound of Formula (XIX) or Formula (XIX′),at least one of R⁶⁵ and R⁶⁶ is deuterium. In certain embodiments of acompound of Formula (XIX) or Formula (XIX′), both of R⁶⁵ and R⁶⁶ aredeuterium.

In certain embodiments of a compound of Formula (XIX) or Formula (XIX′),at least one of R⁶⁵ and R⁶⁶ is deuterium and R⁶⁷ is hydrogen, —CH₃,—CH₂D, —CHD₂, or —CD₃. In certain embodiments of a compound of Formula(XIX) or Formula (XIX'), both of R⁶⁵ and R⁶⁶ are deuterium and R⁶⁷ ishydrogen, —CH₃, —CH₂D, —CHD₂, or —CD₃.

In certain embodiments of a compound of Formula (XIX) or Formula (XIX′),R⁶⁴ is —CD₂CD₃ and R⁶⁷ is H, —CH₃, —CH₂D, —CHD₂, or —CD₃

In certain embodiments of a compound of Formula (XIX) or Formula (XIX′),the compound is (²H₆)dimethyl fumaric acid ester, (²H₃)methyl fumaricacid ester, (²H₃)dimethyl fumaric acid ester, dimethyl fumaric(2,3-²H₂)acid ester, methyl fumaric(2,3-²H₂) acid ester, ethyl fumaric(2,3-²H₂)acid ester, (²H₃)methyl fumaric(2,3-²H₂) acid ester, (²H₆)dimethylfumaric(2,3-²H₂) acid ester, methyl (2-morpholino-2-oxoethyl)fumaric(2,3-²H₂) acid ester, methyl (4-morpholino-l-butyl)fumaric(2,3-²H₂) acid ester, 2-(benzoyloxy)ethyl methyl fumaric(2,3-²H₂)acid ester, 2-(benzoyloxy)ethyl (²H₃)methyl fumaric acid ester,(S)-2-((2-amino-3-phenylpropanoyl)oxy)ethyl methyl fumaric(2,3-²H₂) acidester, or (S)-2-((2-amino-3-phenylpropanoyl)oxy)ethyl (²H₃)methylfumaric acid ester; or a pharmaceutically acceptable salt, clathrate,solvate, or stereoisomer thereof.

In certain embodiments of a compound of Formula (XIX) or Formula (XIX′),the compound is:

or a pharmaceutically acceptable salt, clathrate, solvate, orstereoisomer thereof.

In one embodiment, the compounds of Formula (XIX) and (XIX′) may beprepared using methods known to those skilled in the art, for example,as disclosed in US patent application publication number US 2014-0179779A1.

Deuterated fumarates are useful as active agents for the methodsprovided herein, e.g., treating multiple sclerosis.

In one embodiment, when a particular position in a fumarate isdesignated as having deuterium, it is understood that the abundance ofdeuterium at that position is substantially greater than the naturalabundance of deuterium, which is 0.015%. A position designated as havingdeuterium typically has a minimum deuterium enrichment factor of atleast 3340 (50.1% deuterium incorporation) at each atom designated asdeuterium in said compound.

In other embodiments, a fumarate provided herein has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium), at least 5500 (82.5%deuterium incorporation), at least 6000 (90% deuterium incorporation),at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97%deuterium incorporation), at least 6600 (99% deuterium incorporation),or at least 6633.3 (99.5% deuterium incorporation).

5.1.4 Salts

In particular aspects, included within the scope of the fumaratesdescribed herein are the non-toxic pharmaceutically acceptable salts ofthe fumarates described hereinabove (wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing). Acid addition salts are formed by mixing a solution of afumarate with a solution of a pharmaceutically acceptable non-toxic acidsuch as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate,salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, gluconate, glucaronate, saccharate,formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, and pamoate. Acceptable base saltsinclude aluminum, calcium, lithium, magnesium, potassium, sodium, zinc,and diethanolamine salts.

5.2 Pharmaceutical Compositions

In one embodiment, the fumarate for use in the methods of the inventionis contained in a pharmaceutical composition comprising atherapeutically effective amount of the fumarate and a pharmaceuticallyacceptable carrier, i.e., a pharmaceutically acceptable excipient.

In a specific embodiment, the pharmaceutical composition comprises afumarate; wherein the fumarate is a dialkyl fumarate, a monoalkylfumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate,a prodrug of monoalkyl fumarate, a deuterated form of any of theforegoing, or a clathrate, solvate, tautomer, or stereoisomer of any ofthe foregoing, or a combination of any of the foregoing; with theproviso that a fumarate salt is not present in the pharmaceuticalcomposition.

In a specific embodiment, the pharmaceutical composition comprises afumarate; wherein the fumarate is a dialkyl fumarate, a monoalkylfumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate,a prodrug of monoalkyl fumarate, a deuterated form of any of theforegoing, or a pharmaceutically acceptable salt, clathrate, solvate,tautomer, or stereoisomer of any of the foregoing, or a combination ofany of the foregoing; with the proviso that an ethyl hydrogen fumaratesalt is not present in the pharmaceutical composition.

In a specific embodiment, the pharmaceutical composition comprises afumarate; wherein the fumarate is a dialkyl fumarate, a monoalkylfumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate,a prodrug of monoalkyl fumarate, a deuterated form of any of theforegoing, or a pharmaceutically acceptable salt, clathrate, solvate,tautomer, or stereoisomer of any of the foregoing, or a combination ofany of the foregoing; with the proviso that ethyl hydrogen fumaratecalcium salt, ethyl hydrogen fumarate magnesium salt, ethyl hydrogenfumarate zinc salt, and ethyl hydrogen fumarate copper salt are notpresent in the pharmaceutical composition.

In a specific embodiment, the pharmaceutical composition consistsessentially of DMF and/or monomethyl fumarate.

In a specific embodiment, the pharmaceutical composition comprises DMF.In a specific embodiment, the pharmaceutical composition consistsessentially of DMF. In a specific embodiment, the pharmaceuticalcomposition comprises DMF, with the proviso that ethyl hydrogen fumaratecalcium salt, ethyl hydrogen fumarate magnesium salt, ethyl hydrogenfumarate zinc salt, and ethyl hydrogen fumarate copper salt are notpresent in the pharmaceutical composition. In a specific embodiment, thepharmaceutical composition comprises DMF and/or monomethyl fumarate,with the proviso that ethyl hydrogen fumarate calcium salt, ethylhydrogen fumarate magnesium salt, ethyl hydrogen fumarate zinc salt, andethyl hydrogen fumarate copper salt are not present in thepharmaceutical composition. In a specific embodiment, the pharmaceuticalcomposition comprises DMF, with the proviso that no additional fumarateother than DMF or monomethyl fumarate is present.

In a specific embodiment, the pharmaceutical composition can be an oraldosage form, e.g., a solid oral dosage form. In a specific embodiment,the pharmaceutical composition is a tablet, capsule, or capsulecontaining microtablets. Optionally, the tablet or microtablets areenterically coated. In a specific embodiment, the pharmaceuticalcomposition is in the form of enterically coated tablets or microtablets(optionally contained in a capsule), which, once the enteric coating isdissolved in the gastro-intestinal tract, act as immediate releasedosage forms.

In another specific embodiment, the pharmaceutical composition is acontrolled, or sustained, release composition, optionally entericallycoated.

The pharmaceutical preparations described herein are manufactured in amanner which is itself known, for example, by means of conventionalmixing, granulating, dragee-making, dissolving, or lyophilizingprocesses. Thus, pharmaceutical preparations for oral use may beobtained by combining the fumarates with solid excipients, optionallygrinding the resulting mixture and processing the mixture of granules,after adding suitable auxiliaries, if desired or necessary, to obtaintablets or dragee cores.

In general, when the drug load (or weight percent of an activeingredient) of a solid oral dosage form (e.g., a tablet or amicrotablet) is significantly increased, the weight percent of theexcipient(s) must decrease (especially if the size of the solid oraldosage form remains the same). The solid oral dosage form often becomesunstable due to the decrease in the amount of excipient(s), e.g.,binders, that function to hold all the components together in a cohesivemix. It is unexpected that increasing the amount of DMF (e.g., from 120mg to 240 mg) and decreasing the amount of binder, while keeping thesize of the solid oral dosage form (e.g., capsule size) to be the same,the strength or integrity of solid dosage form does not suffer.

Suitable excipients are, in particular, fillers such as saccharides, forexample lactose or sucrose, mannitol or sorbitol, cellulose preparationsand/or calcium phosphates, for example tricalcium phosphate or calciumhydrogen phosphate, as well as binders such as starch paste, using, forexample, maize starch, wheat starch, rice starch, potato starch,gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose,sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,disintegrating agents may be added such as the above-mentioned starchesand also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar,or alginic acid or a salt thereof, such as sodium alginate. Auxiliariesare, above all, flow-regulating agents and lubricants, for example,silica, talc, stearic acid or salts thereof, such as magnesium stearateor calcium stearate, and/or polyethylene glycol. Dragee cores areprovided with suitable coatings which, if desired, are resistant togastric juices. For this purpose, concentrated saccharide solutions maybe used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquersolutions and suitable organic solvents or solvent mixtures. In order toproduce coatings resistant to gastric juices, solutions of suitablecellulose preparations such as acetylcellulose phthalate orhydroxypropymethyl-cellulose phthalate, are used. Dye stuffs or pigmentsmay be added to the tablets or dragee coatings, for example, foridentification or in order to characterize combinations of activecompound doses.

In one embodiment, the pharmaceutical preparations described hereincomprise a capsule containing the agent or pharmaceutical compositiondescribed herein in the form of an enteric-coated microtablet. Thecoating of the microtablet may be composed of different layers. Thefirst layer may be a methyacrylic acid-methyl methacrylatecopolymer/isopropyl solution which isolates the tablet cores frompotential hydrolysis from the next applied water suspensions. Theenteric coating of the tablet may then be conferred by an aqueousmethacrylic acid-ethyl acrylate copolymer suspension.

In another embodiment, is provided a composition comprising afumarate,such as dimethyl fumarate, and one or more excipients, whereina total amount of the fumarate in the composition ranges, for example,from about 43% w/w to about 95% w/w, based on the total weight of thecomposition, excluding the weight of any coating.

The total amount of the fumarate, such as dimethyl fumarate, in thecomposition described herein can range, for example, from about 43% w/wto about 95% w/w, from about 50% w/w to about 95% w/w, from about 50%w/w to about 85% w/w, from about 55% w/w to about 80% w/w, from about60% w/w to about 75% w/w, from about 60% w/w to about 70% w/w, or fromabout 65% w/w to about 70% w/w, based on the total weight of thecomposition, excluding the weight of any coating.

The composition described herein can comprise the fumarate, such asdimethyl fumarate, for example, in about 43% w/w, about 45% w/w, about50% w/w, about 55% w/w, about 60% w/w, about 65% w/w, about 70% w/w,about 75% w/w, about 80% w/w, about 90% w/w, or about 95% w/w, based onthe weight of the composition, excluding the weight of any coating. Forexample, the composition can contain about 65% to about 95% w/w (e.g.,65% w/w) of DMF.

Some or all of the fumarate, such as dimethyl fumarate, in thecomposition can have a particle size of 250 microns or less. Forexample, and without being limiting, at least 80%, at least 90%, atleast 95%, at least 97%, or at least 99% of the fumarate, such asdimethyl fumarate, in the composition can have a particle size of 250microns or less. Particle size can be measured, for example, by sieveanalysis, air elutriation analysis, photoanalysis, electrical countingmethods, electroresistance counting methods, sedimentation techniques,laser diffraction methods, acoustic spectroscopy, or ultrasoundattenuation spectroscopy. In one embodiment, the particle size ismeasured using laser diffraction methods.

The composition described herein can comprise a total amount ofexcipient(s), for example, in an amount of about 5.0% w/w to about 57%w/w, based on the total weight of the composition, excluding the weightof any coating.

The composition described herein can comprise a total amount ofexcipient(s) in an amount ranging, for example, from about 5% w/w toabout 57% w/w, from about 15% w/w to about 57% w/w, from about 20% w/wto about 57% w/w, from about 25% w/w to about 57% w/w, from about 30%w/w to about 57% w/w, from about 35% w/w to about 57% w/w, from about40% to about 57% w/w, from about 45% w/w to about 57% w/w, from about50% w/w to about 57% w/w, from about 55% w/w to about 57% w/w, fromabout 5% w/w to about 55% w/w, from about 5% w/w to about 50% w/w, fromabout 5% w/w to about 45% w/w, from about 5% w/w to about 40% w/w, fromabout 5% w/w to about 35% w/w, from about 5% w/w to about 30% w/w, fromabout 5% w/w to about 25% w/w, from about 5% w/w to about 20% w/w, fromabout 5% w/w to about 15% w/w, from about 15% w/w to about 55% w/w, fromabout 20% w/w to about 50% w/w, from about 25% w/w to about 45% w/w,from about 30% w/w to about 40% w/w, from about 35% to about 40% w/w,based on the total weight of the composition, excluding the weight ofany coating.

The excipient(s) can be, for example, one or more selected from thegroup consisting of a filler (or a binder), a glidant, a disintegrant, alubricant, or any combination thereof.

The number of excipients that can be included in a composition is notlimited.

Examples of fillers or binders include, but are not limited to, ammoniumalginate, calcium carbonate, calcium phosphate, calcium sulfate,cellulose, cellulose acetate, compressible sugar, confectioner's sugar,dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose,glyceryl palmitostearate, hydrogenated vegetable oil type I, isomalt,kaolin, lactitol, lactose, mannitol, magnesium carbonate, magnesiumoxide, maltodextrin, maltose, mannitol, medium chain triglycerides,microcrystalline cellulose, polydextrose, polymethacrylates,simethicone, sodium alginate, sodium chloride, sorbitol, starch,sucrose, sugar spheres, sulfobutylether beta- cyclodextrin, talc,tragacanth, trehalsoe, polysorbate 80, and xylitol. In one embodiment,the filler is microcrystalline cellulose. The microcrystalline cellulosecan be, for example, PROSOLV SMCC® 50, PROSOLV SMCC® 90, PROSOLV SMCC®HD90, PROSOLV SMCC® 90 LM, and any combination thereof.

Examples of disintegrants include, but are not limited to, hydroxypropylstarch, alginic acid, calcium alginate, carboxymethylcellulose calcium,carboxymethylcellulose sodium, powdered cellulose, chitosan, colloidalsilicon dioxide, croscarmellose sodium, crospovidone, docusate sodium,guar gum, hydroxypropyl cellulose, low substituted hydroxypropylcellulose, magnesium aluminum silicate, methylcellulose,microcrystalline cellulose, polacrilin potassium, povidone, sodiumalginate, sodium starch glycolate, starch, and pregelatinized starch. Inone embodiment, the disintegrant is croscarmellose sodium.

Examples of glidants include, but are not limited to, calcium phosphate,calcium silicate, powdered cellulose, magnesium silicate, magnesium trisilicate, silicon dioxide, talcum and colloidal silica, and colloidalsilica anhydrous. In one embodiment, the glidant is colloidal silicaanhydrous, talc, or a combination thereof.

Examples of lubricants include, but are not limited to, canola oil,hydroxyethyl cellulose, lauric acid, leucine, mineral oil, poloxamers,polyvinyl alcohol, talc, oxtyldodecanol, sodium hyaluronate,sterilizable maize starch, triethanolamine, calcium stearate, magnesiumstearate, glycerin monostearate, glyceryl behenate, glycerylpalmitostearate, hydrogenated castor oil, hydrogenated vegetable oiltype I, light mineral oil, magnesium lauryl sulfate, medium-chaintriglycerides, mineral oil, myristic acid, palmitic acid, poloxamer,polyethylene glycol, potassium benzoate, sodium benzoate, sodiumchloride, sodium lauryl sulfate, stearic acid, talc, and zinc stearate.In one embodiment, the lubricant is magnesium stearate.

The composition described herein can comprise a total amount offiller(s) in an amount ranging from about 3.5% w/w to about 55% w/w ofthe composition, based on the total weight of the composition, excludingthe weight of any coating.

The filler(s) can be comprised in the composition described herein, forexample, in a total amount, for example, ranging from about 5% w/w toabout 55% w/w, from about 10% w/w to about 55% w/w, from about 15% w/wto about 55% w/w, from about 20% w/w to about 55% w/w, from about 25%w/w to about 55% w/w, from about 30% w/w to about 55% w/w, from about35% w/w to about 55% w/w, from about 40% w/w to about 55% w/w, fromabout 3.5% w/w to about 55% w/w, from about 3.5% to about 50%, fromabout 3.5% w/w to about 40% w/w, from about 3.5% w/w to about 30% w/w,from about 3.5% w/w to about 25% w/w, from about 3.5% w/w to about 20%w/w, from about 3.5% w/w to about 15% w/w, from about 15% w/w to about40% w/w, from about 20% w/w to about 35% w/w, or from about 25% w/w toabout 30% w/w, based on the total weight of the composition, excludingthe weight of any coating.

The filler(s) can be comprised in the composition, for example, in atotal amount of about 5% w/w, about 7% w/w, about 10% w/w, about 12%w/w, about 14% w/w, about 16% w/w, about 18% w/w, about 20% w/w, about22% w/w, about 24% w/w, about 26% w/w, about 28% w/w, about 30% w/w,about 32% w/w, about 34% w/w, about 36% w/w, about 38% w/w, about 40%w/w, about 42% w/w, about 44% w/w, about 46% w/w, about 48% w/w, about50% w/w, about 52% w/w, about 54% w/w, or about 55% w/w, based on thetotal weight of the composition, excluding the weight of any coating.

The composition described herein can comprise a total amount ofdisintegrant(s), for example, in an amount ranging from about 0.2% w/wto about 20% w/w, based on the total weight of the composition,excluding the weight of any coating.

The disintegrant(s) can be contained in the composition, for example, ina total amount ranging from about 0.2% w/w to about 19% w/w, about 0.2%w/w to about 15% w/w, about 0.2% w/w to about 12% w/w, about 0.2% w/w toabout 6% w/w, about 0.2% w/w to about 5% w/w, about 0.2% w/w to about 4%w/w, about 0.2% w/w to about 3% w/w, about 0.2% w/w to about 2% w/w,about 0.2% w/w to about 20% w/w, about 3% w/w to about 20% w/w, about 4%w/w to about 20% w/w, about 5% w/w to about 20% w/w, about 6% w/w toabout 20% w/w, about 7% w/w to about 20% w/w, about 8% w/w to about 20%w/w, about 9% w/w to about 20% w/w, about 2% w/w to about 20% w/w, orabout 3% w/w to about 20% w/w, based on the weight of the composition,excluding the weight of any coating.

The disintegrant(s) can be contained in the composition, for example, ina total amount of about 1% w/w, about 2% w/w, about 3% w/w, about 4%w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9%w/w, about 10% w/w, about 12% w/w, about 14% w/w, about 16% w/w, about18% w/w, or about 19% w/w, based on the total weight of the composition,excluding the weight of any coating.

The glidant(s) can be contained in the composition, for example, in atotal amount ranging from about 0.1% w/w to about 9.0% w/w, based on thetotal weight of the composition, excluding the weight of any coating.

The glidant(s) can be contained in the composition, for example, in atotal amount ranging from about 0.1% w/w to about 9.0% w/w, from about0.1% w/w to about 8% w/w, from about 0.1% w/w to about 6% w/w, fromabout 0.1% w/w to about 4% w/w, from about 0.1% w/w to about 2.8% w/w,from about 0.1% w/w to about 2.6% w/w, from about 0.1% w/w to about 2.4%w/w, from about 0.1% w/w to about 2.2% w/w, from about 0.1% w/w to about2.0% w/w, from about 0.1% w/w to about 1.8% w/w, from about 0.1% w/w toabout 1.6% w/w, from about 0.1% to about 1.4% w/w, from about 0.1% w/wto about 1.2% w/w, from about 0.1% w/w to about 1.0% w/w, from about0.1% w/w to about 0.8% w/w, from about 0.1% w/w to about 0.4% w/w, fromabout 0.2% w/w to about 3.0% w/w, from about 0.4% w/w to about 3.0% w/w,from about 0.6% w/w to about 3.0% w/w, from about 0.8% w/w to about 3.0%w/w, from about 1.0% w/w to about 3.0% w/w, from about 1.2% w/w to about9.0% w/w, from about 1.4% w/w to about 9.0% w/w, from about 1.6% w/w toabout 9.0%, from about 1.8% w/w to about 9.0% w/w, from about 2.0% w/wto about 9.0% w/w, from about 2.2% w/w to about 9.0% w/w, from about2.4% w/w to about 9.0% w/w, from about 2.6% w/w to about 9.0% w/w, fromabout 2.8% w/w to about 9.0% w/w, from about 3.0% w/w to about 9.0% w/w,from about 4.0% w/w to about 9.0% w/w, from about 5.0% w/w to about 9.0%w/w, from about 6.0% w/w to about 9.0% w/w, from about 7.0% w/w to about9.0% w/w, from about 8.0% w/w to about 9.0% w/w, from about 0.5% w/w toabout 2.5% w/w, or from about 1.0% w/w to about 2.0% w/w, based on thetotal weight of the composition, excluding the weight of any coating.

The glidant(s) can be contained in the composition, for example, in atotal amount of about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8%w/w, about 0.9% w/w, about 1.0% w/w, about 1.2% w/w, about 1.4% w/w,about 1.6% w/w, about 1.8% w/w, about 2.0% w/w, about 2.2% w/w, about2.4% w/w, about 2.6% w/w, about 2.8% w/w, about 3% w/w, about 4% w/w,about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, or about 9% w/w,based on the total weight of the composition, excluding the weight ofany coating.

The lubricant(s) can be contained in the composition, for example, in atotal amount ranging from about 0.1% w/w to about 3.0% w/w, based on thetotal weight of the composition, excluding the weight of any coating.

The lubricant(s) can be contained in the composition, for example, in atotal amount ranging from about 0.1% w/w to about 2% w/w, about 0.1% w/wto about 1% w/w, from about 0.1% w/w to about 0.7% w/w, from about 0.1%w/w to about 0.6% w/w, from about 0.1% w/w to about 0.5% w/w, from about0.1% w/w to about 0.4% w/w, from about 0.1% w/w to about 0.3% w/w, fromabout 0.1% w/w to about 0.2% w/w, from about 0.2% w/w to about 3.0% w/w,from about 0.3% w/w to about 3.0% w/w, from about 0.4% w/w to about 3.0%w/w, from about 0.5% w/w to about 3.0% w/w, from about 0.6% w/w to about3.0% w/w, from about 0.7% w/w to about 3.0% w/w, from about 0.8% w/w toabout 3.0% w/w, from about 0.9% w/w to about 3.0% w/w, from about 1% w/wto about 3.0% w/w, from about 2% w/w to about 3% w/w, from about 0.2%w/w to about 0.7% w/w, from about 0.3% w/w to about 0.6% w/w, or fromabout 0.4% w/w to about 0.5% w/w, based on the total weight of thecomposition, excluding the weight of any coating.

The lubricant(s) can be contained in the composition, for example, in atotal amount of about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8%w/w, about 0.9% w/w, about 1.0% w/w, about 2.0% w/w, or about 3.0% w/w,based on the total weight of composition, excluding the weight of anycoating.

In some embodiments, for example, the composition described hereincomprises one or more fillers in a total amount ranging from about 3.5%w/w to about 55% w/w, one or more disintegrants in a total amountranging from about 0.2% w/w to about 20% w/w, one or more glidants in atotal amount ranging from about 0.1% w/w to about 9.0% w/w, and one ormore lubricants in a total amount ranging from about 0.1% w/w to about3.0% w/w.

In some embodiments, for example, the composition described hereincomprises a filler, a disintegrant, a glidant, and a lubricant. In someembodiments, the filler is microcrystalline cellulose, the disintegrantis croscarmellose sodium, the glidant is colloidal silica anhydrous, andthe lubricant is magnesium stearate. In other embodiments, the filler ismicrocrystalline cellulose, the disintegrant is croscarmellose sodium,the glidant is a combination of colloidal silica anhydrous and talc, andthe lubricant is magnesium stearate.

The ingredients in the composition described herein can be, for example,homogeneous or heterogeneously mixed. The composition ingredients canbe, for example, mixed by any known method including shaking, stirring,mixing with forced air, mixing in a spinning container, and the like.The composition ingredients can be, for example, mixed all at once, orwith progressive addition of one or more ingredients. The compositioningredients can be mixed in any order, for example, individually, ingroups, or as a blend of all of the ingredients. For example, theglidant(s) can be mixed with the DMF and/or disintegrant(s) prior tomixing with any or all of the filler(s) and/or lubricants. The blend canalso be prepared by mixing DMF, disintegrant(s) (e.g., croscarmellosesodium) and a portion of binder (e.g., microcrystalline cellulose)before then passing through a screen or sieve. The remaining binder canbe mixed with lubricant(s) (e.g., magnesium stearate) before passingthrough a screen or sieve. These two mixtures can then be combined andmixed before adding glidant(s) (e.g., silica colloidal anhydrous). Theglidant(s) can also be added to one or both of the aforementionedmixtures before they are combined and mixed to produce the final blend.

The composition described herein can have a flowability index, forexample, ranging from about 8 mm to about 24 mm. For example, theflowability index can range from about 12 mm to about 22 mm, from about12 mm to about 20 mm, from about 12 mm to about 18 mm, from about 12 mmto about 16 mm, from about 12 mm to about 14 mm, from about 14 mm toabout 24 mm, from about 16 mm to about 24 mm, from about 18 mm to about24 mm, from about 20 mm to about 24 mm, from about 22 mm to about 24 mm,from about 14 mm to about 22 mm, or from about 16 mm to about 20 mm.

The flowabilty index can be, for example, less than 18 mm (e.g., about 8mm, about 12 mm, about 14 mm, about 16 mm) with an amount of glidant(s)ranging from about 0.1% w/w to about 2.0% w/w (e.g., 1.0% w/w).

The flowability index can be measured, for example, on a FLODEX device(manufactured by Hanson Research). The following protocol, for example,can be employed: A powder sample (e.g., 50 g) is loaded into thecylinder on the FLODEX device such that the powder is within about 1 cmfrom the top of the cylinder. A minimum of 30 seconds is allowed to passbefore testing commences. Starting with a 16 mm flow disk, the releaselever is slowly turned until the closure drops open without vibration.The test is positive when the open hole at the bottom is visible whenlooking down from the top. If a positive result is obtained, the test isrepeated with smaller and smaller disk holes until the test is negative.For negative results, the size of the flow disk hole is increased untilthe test is positive. The flowability index is the diameter of thesmallest hole through which the sample will pass for three successivetests.

The composition can have, for example, a compressibility index rangingfrom about 15% to about 28%. The compressibility index can range, forexample, from 17% to about 28%, from about 19% to about 28%, from about21% to about 28%, from about 23% to about 28%, from about 25% to about28%, from about 15% to about 26%, from about 15% to about 24%, fromabout 15% to about 22%, from about 15% to about 20%, from about 15% toabout 18%, from about 17% to about 26%, from about 19% to about 24%, orfrom about 20% to about 22%.

The composition can have a compressibility index, for example, of about16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%,about 23%, about 24%, about 25%, about 26%, or about 27%.

The compressibility index can be defined, for example, by the formula:(((V_(o)-V_(f))/V_(o))×100%) where V_(o) is unsettled apparent volume ofthe particle and V_(f) is the final tapped volume of the powder. Thecompressibility index can be determined, for example, as follows: powderis placed in a container and the powder's unsettled apparent volume(V_(o)) is noted. Next, the powder is tapped until no further volumechanges occur. At this point, the final tapped volume of the powder ismeasured (V_(f)). The compressibility index is then calculated by usingthe formula above.

In some embodiments, the composition can be in the form of a powder (notcompressed) or a compact (compressed). The shape of the compact is notlimited and can be, for example, cubic, spherical, or cylindrical (e.g.,disc-shaped).

The compact can be, for example, in the form of tablets, caplets, ormicrotablets. The compact can be prepared by any means known in the art.For example, if the compact is in the form of microtablets, themicrotablets can be made by compressing the composition described aboveusing any known method, such as using a rotary tablet press equippedwith a multi-tip tooling and having concave tips.

Multi-tip tableting tools, for example, can be used. For example, amulti-tip tool having from about 16 tips to about 40 tips using, forexample, about 2 mm diameter tips. In this situation, appliedcompressing force can be expressed as an average kN/tip. For example, anapplied compressing force of 2 kN used with a 16 multi-tip tool yieldsan applied compressing force of about 0.125 kN/tip. Similarly, anapplied compressing force of about 15 kN used with a 16 multi-tip toolyields an applied compressing force of about 0.94 kN per tip.

The microtablets can have a mean diameter (excluding any coatings), forexample, ranging from about 1 mm to about 3 mm. For example, themicrotablets can have a mean diameter ranging from about 1 mm to about2.5 mm. The microtablets can have a mean diameter of about 1.0 mm, about2.0 mm, or about 3.0 mm.

Compact tensile strength can be determined by any means known in theart. For example, the following protocol could be employed. First,compact(s) are compressed to about 360 mg weight using an instrumentedrotary tablet press equipped to measure compression force with roundflat tooling of approximately 10 mm diameter. Next, measure thediametrial crushing strengthusing a suitable tablet hardness tester andthen calculate tensile strength by the procedure reported by Newton(Newton, J. M., Journal of Pharmacy and Pharmacology, 26: 215-216(1974)). See also Pandeya and Puri, KONA Powder and Particle Journal,30: 211-220 (2013), Jarosz and Parrott, J. Pharm. Sci. 72(5):530-535(1983), and Podczeck, Intl. J. Pharm. 436:214-232 (2012).

The composition described herein, in the form of a compact, can have atensile strength equal to or greater than 1.5 MPa at an applied orcompaction pressure of about 100 MPa. For example, the tensile strengthcan range from about 2.0 to about 5.0 MPa (e.g., from about 2.5 to about4.5 MPa, from about 3.0 to about 4.5 MPa or from about 3.5 to about 4.5MPa) at an applied or compaction pressure of about 100 MPa. For example,the tensile strength can be about 4.0 MPa at an applied or compactionpressure of about 100 MPa.

The compact in the form of one or more microtablets produced using 16multi-tip tooling can have a hardness or breaking strength or crushingstrength ranging from about 8 N to about 35 N when the microtablet isformed by a compression force ranging from 2 kN to about 15 kN and themicrotablet has a 2 mm diameter, a thickness of 2 mm, and a 1.8 mmradius of the convex surface. In one embodiment, microtablets eachhaving a 2 mm diameter, a thickness of 2 mm, and a 1.8 mm radius of theconvex surface have a hardness ranging from about 17 N to about 24 N fora compression force of about 4 kN to about 7 kN. The hardness can be,for example, of from about 23 N to about 27 N (e.g., about 24 N, about25 N, or about 26 N) for a compression force of about 10 kN to about 15kN. Hardness or breaking strength or crushing strength can be determinedfor example, using an Erweka tester or a Schleuniger tester as describedin Lachman, L. et al., The Theory & Practice of Industiral Pharmacology(3rd ed. 1986), p. 298.

In some embodiments, the composition can be optionally coated orpartially coated by one or more coatings. The coating(s) can be pHindependent or pH dependent. The coating(s) can be, for example, entericcoatings, seal coatings, or combinations of enteric coatings and sealcoatings.

The seal coating can contain, for example, one or more plasticizers, oneor more copolymers, one or more polymers, or combinations thereof.

The plasticizer can be, for example, one or more of acetyltributylcitrate, acetyltriethyl citrate, benzyl benzoate, cellulose acetatephthalate, chlorbutanol, dextrin, dibutyl phthalate, dibutyl secacate,diethyl phthalate, dimethyl phthalate, glycerin, glycerin monostearate,hypromellose phthalate, mannitol, mineral oil an lanolin alcohols,palmitic acid, polyethylene glycol, polyvinyl acetate phthalate,propylene glycol, 2-pyrrolidone, sorbitol, stearic acid, triacetin,tributyl citrate, triethanolamine, and triethyl citrate.

The copolymer can be, for example, a methacrylic acid-methacrylatecopolymer or a methacrylic acid-ethylacrylate copolymer.

Additionally, the seal coating can contain one or more polymers, forexample, cellulose derivatives such as hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl and methylcellulose,polyvinylpyrrolidone, a polyvinylpyrrolidone/vinyl acetate copolymer,ethyl cellulose, and ethyl cellulose aqueous dispersions (AQUACOAT®,SURELEASE®), EUDRAGIT® RL 30 D, OPADRY®, EUDRAGIT® S, EUDRAGIT® L, andthe like.

If present in the seal coating, the total amount of one or morecopolymer(s) and/or one or more polymer(s) in the seal coating canrange, for example, from a positive amount greater than 0% w/w to about100% w/w, based on the weight of the seal coating. The amount of one ormore copolymer(s) and/or one or more polymer(s) in the seal coating canrange, for example, from about 10% w/w to about 100% w/w, from about 20%w/w to about 100% w/w, from about 30% w/w to about 100% w/w, from about40% w/w to about 100% w/w, from about 50% w/w to about 100% w/w, fromabout 60% w/w to about 100% w/w, from about 70% w/w to about 100% w/w,from about 80% w/w to about 100% w/w, or from about 90% w/w to about100% w/w, based on the weight of the seal coating.

The amount of one or more copolymer(s) and/or one or more polymer(s) inthe seal coating can be, for example, about 10% w/w, about 20% w/w,about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50%w/w, about 55% w/w, about 60% w/w, about 65% w/w, about 70% w/w, about75% w/w, about 80% w/w, about 85% w/w, about 90% w/w, or about 95% w/w,based on the weight of the seal coating.

If present in the seal coating, the mean amount of plasticizer in theseal coating can range, for example, from a positive amount greater than0% w/w to about 70% w/w, based on the weight of the seal coating.

The enteric coating can contain, for example, one or more plasticizers,one or more fillers, one or more lubricants, one or more copolymers, oneor more polymers, and any combinations thereof.

The plasticizer(s) in the enteric coat can be the same or different thanany plasticizer(s) in a seal coat, if present, and can be one of more ofthe plasticizers listed above.

The filler(s) in the enteric coat can be the same or different than anyfiller(s) in the composition. Additionally, the filler(s) in the entericcoat can be the same or different than any filler(s) in a seal coat, ifpresent, and can be one or more of the fillers listed above.

The lubricant(s) in the enteric coat can be the same or different thanany lubricant(s) in the composition. Additionally, the lubricant(s) inthe enteric coat can be the same or different than the copolymer(s) in aseal coat, if present, and can be one or more of the lubricants listedabove. In one embodiment, the lubricant is talcum that is optionallymicronized.

The copolymer(s) in the enteric coat can be the same or different thanthe copolymer(s) in a seal coat, if present, and can be one or more ofthe copolymer(s) listed above. In one embodiment, the enteric coatcontains one or more of a methyl acrylate-methylmethacrylate-methacrylic acid copolymer (EUDRAGIT® FS 30 D), amethacrylic acid-methyl methacrylate copolymer and a methacrylicacid-ethyl acetate copolymer.

The enteric polymers used in the composition described herein can bemodified by mixing or layering with other known coating products thatare not pH sensitive. Examples of such coating products include ethylcellulose, hydroxylpropyl cellulose, neutral methacrylic acid esterswith a small portion of trimethylammonioethyl methacrylate chloride,sold currently under the trade names EUDRAGIT® RS and EUDRAGIT® RL; aneutral ester dispersion without any functional groups, sold under thetrade names EUDRAGIT® NE 30 D; and other pH independent coatingproducts.

The total amount of the copolymer(s) and/or polymer(s) in the entericcoating can range, for example, from about 25% w/w to about 100% w/w,based on the weight of the enteric coating.

If present in an enteric coating, the total amount of lubricant(s) inthe enteric coating can range, for example, from a positive amountgreater than 0% w/w to about 58% w/w, based on the weight of the entericcoating.

If present in an enteric coating, the total amount of filler(s) in theenteric coating can range, for example, from a positive amount greaterthan 0% w/w to about 5.0% w/w, based on the weight of the entericcoating.

Solvents for applying the coating materials, can be, but are not limitedto, water, acetone, hexane, ethanol, methanol, propanol, isopropanol,butanol, isobutanol, sec-butanol, tert- butanol, dichlormethane,trichloromethane, chloroform, and the like.

Coatings can be applied by any known means, including spraying. In someembodiments, the compositions are coated or partially coated with one ormore seal coatings, for example one, two, three or more seal coatings.In some embodiments, the compositions are coated or partially coatedwith one or more enteric coatings, for example one, two, three or moreenteric coatings. In some embodiments, the compositions are coated withone or more seal coatings and one or more enteric coatings. In someembodiments, the compositions are coated with one seal coating and oneenteric coating.

In a specific embodiment, the pharmaceutical composition is a tablet,for example, the tablet set forth in Table 2 and further coated with aseal coating solution and an enteric coating solution according toFormula A as set forth in Table 3 (See Example 1, Section 6.1 infra).

In a specific embodiment, the pharmaceutical composition is a tablet,for example, the tablet set forth in Table 2 and further coated with aseal coating solution and an enteric coating solution according toFormula B as set forth in Table 3 (See Example 1, Section 6.1 infra).

In a specific embodiment, the pharmaceutical composition is the same asin TECFIDERA®. In another specific embodiment, the pharmaceuticalcomposition is the same as in FUMADERM®. In another specific embodiment,the pharmaceutical composition contains different fumarates from thosefumarates in FUMADERM®.

In one embodiment, the pharmaceutical composition is in the form of atablet or a capsule. In one embodiment, the pharmaceutical compositionis in the form of an enterically coated tablet. In one embodiment, thepharmaceutical composition is in the form of an enterically coatedmicrotablets.

5.3 Dosing Regimens

This disclosure provides dosing regimens for administering the fumarateas described herein. The fumarates and pharmaceutical compositionsdescribed herein may be administered by any means that achieve theirintended purpose. For example, administration may be by parenteral,subcutaneous, intramuscular, intraperitoneal, transdermal, buccal,intrathecal, intracranial, intranasal, or topical routes. In oneembodiment, the administering is done orally. The dosage administeredwill be dependent upon the age, health, and weight of the recipient,kind of concurrent treatment, if any, frequency of treatment, and thenature of the effect desired.

The amount of fumarate that can be combined with the carrier materialsto produce a single dosage form will vary depending upon the hosttreated, and the particular mode of administration. It should beunderstood, however, that a specific dosage and treatment regimen forany particular subject will depend upon a variety of factors, includingthe activity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, rate of excretion,drug combination, and the judgment of the treating physician and theseverity of the particular disease being treated. The amount of fumaratecan also depend upon the therapeutic or prophylactic agent, if any, withwhich the agent is co-administered.

A composition comprising a total amount of dimethyl fumarate (DMF)ranging from about 43% w/w to about 95% w/w (e.g., from about 50% w/w toabout 80% w/w or from about 60% w/w to about 70% w/w) and one or moreexcipients formulated in such a manner that about 160 mg of DMF to about500 mg of DMF (e.g., about 240 mg to about 480 mg DMF) can be includedin a single dosage form that can be administered, for example, once perday (QD), twice per day (BID), or thrice per day (TID). For example, acapsule (e.g., size 0) can contain about 240 mg of DMF. As anotherexample, a capsule can contain about 480 mg of DMF.

When the fumarate is administered to a human, the compound may quicklymetabolize to MMF. The pharmacokinetics properties (e.g., C_(max) andAUC) can be therefore measured based on the concentration of MMF in theplasma after administration. The pharmacokinetics properties can bedetermined after single dosing or at steady state. In some embodiments,subjects orally administered a dosage form described above containing afumarate or a pharmaceutically acceptable salt, clathrate, solvate,tautomer, or stereoisomer thereof exhibit a time to maximum plasma MMFconcentration (T_(max)) of, for example, from about 1.5 hours to about3.5 hours, from about 1.75 hours to about 3.25 hours, or from about 2hours to about 2.5 hours.

In some embodiments, subjects orally administered a dosage formdescribed above containing a fumarate exhibit a mean MMF plasma areaunder the curve 0-12 (AUC₀.₁₂) of about 2.36 h.mg/L to about 5.50h.mg/L, from about 2.75 h.mg/L to about 5.10 h.mg/L, or from about 3.14h.mg/L to about 4.91 h.mg/L. In one embodiment, subjects exhibit a meanAUC₀-₁₂ of about 3.93 h.mg/L.

In some embodiments, subjects orally administered a dosage formdescribed above containing a fumarate exhibit a mean MMF plasma areaunder the curve 0-infinity (AUC_(0-infinity)) of about 2.4 h.mg/L toabout 5.6 h.mg/L, from about 2.75 h.mg/L to about 5.10 h.mg/L, or fromabout 3.14 h.mg/L to about 4.91 h.mg/L. In one embodiment, subjectsexhibit a mean AUC_(0-infinity) of about 3.93 h.mg/L.

In some embodiments, subjects orally administered a dosage formdescribed above containing a fumarate twice daily exhibit a mean MMFplasma overall area under the curve of about 4.81 h.mg/mL to about 11.2h.mg/mL, or from about 6.40 h.mg/L to about 10.1 h.mg/L. In oneembodiment, subjects exhibit a mean AUC_(overall) of about 8.02 h.mg/Lwhen orally administered the dosage forms twice daily.

In some embodiments, subjects orally administered a dosage formdescribed above containing a fumarate exhibit a mean MMF plasmaconcentration (C_(max)) of from about 1.45 mg/L to about 3.39 mg/L, fromabout 1.69 mg/L to about 3.15 mg/L, or from about 1.93 mg/L to about3.03 mg/L. In one embodiment, subjects exhibit a mean C_(max) of about2.42 mg/L.

In one embodiment, subjects orally administered a dosage form describedabove containing a fumarate exhibit a mean C. of about 1.02 mg/L toabout 2.41 mg/L, or about 1.37 mg/L to about 2.15 mg/L. In oneembodiment, subjects exhibit a mean C_(max) of about 1.72 mg/L whenorally administered the dosage forms twice daily.

Additionally, subjects orally administered a dosage form described abovecontaining a fumarate can exhibit one or more of the followingpharmacokinetic parameters: (a) a mean plasma MMF T_(max) of from about1.5 hours to about 3.5 hours; (b) a mean plasma MMF C_(max) ranging fromabout 1.03 mg/L to about 3.4 mg/L; (c) a mean plasma MMF AUC_(overall)ranging from about 4.81 h.mg/L to about 11.2 h.mg/L; (d) a mean plasmaMMF AUC₀₋₁₂ ranging from about 2.4 h.mg/L to about 5.5 h.mg/L; and (e) amean AUC_(0-infinity) ranging from about 2.4 h.mg/L to about 5.6 h.mg/L.

In some embodiments, the compounds and pharmaceutical compositionsdescribed herein can be administered in an amount ranging from about 1mg/kg to about 50 mg/kg (e.g., from about 2.5 mg/kg to about 20 mg/kg orfrom about 2.5 mg/kg to about 15 mg/kg). The amount of the compounds andpharmaceutical compositions described herein administered will alsovary, as recognized by those skilled in the art, dependent on route ofadministration, excipient usage, and the possibility of co-usage withother therapeutic treatments including use of other therapeutic agents.

For example, the compounds and pharmaceutical compositions describedherein can be administered to a subject, for example orally, in anamount of from about 0.1 g to about 1 g per day, or for example, in anamount of from about 100 mg to about 800 mg per day.

The amount of compounds and pharmaceutical compositions described hereinmay be administered once a day or in separate administrations of 2, 3,4, 5 or 6 equal doses per day.

In addition to administering the agent as a raw chemical, the agentsdescribed herein may be administered as part of a pharmaceuticalpreparation containing suitable pharmaceutically acceptable carrierscomprising excipients and auxiliaries which facilitate processing of theagents into preparations which may be used pharmaceutically. Forexample, the preparations, particularly those preparations which may beadministered orally, such as tablets, dragees, and capsules, and alsopreparations which may be administered rectally, such as suppositories,as well as suitable solutions for administration by injection or orally,contain from about 0.01 to 99 percent, preferably from about 0.25 to 75percent of fumarate(s), together with the excipient.

In one embodiment, the composition is in the form of a dosage form, suchthat one composition provides the total DMF dose. In other embodiments,the dosage form contains multiple compositions to provide the total DMFdose. For example, a dosage form may contain multiple compacts, such asmicrotablets, to provide the desired total DMF dose.

If the dosage form contains multiple compacts, such as multiplemicrotablets, to provide the required total DMF dose, the compacts inthe dosage form can differ from one another. For example, the dosageform can contain two or more different microtablet types (e.g., thecapsule can contain one group of microtablets coated with only anenteric coating and a second group of microtablets coated with only aseal coating, or one group coated with an enteric coating with a lowerpH release and the other coated with an enteric coating with a higher pHrelease).

In some embodiments, the composition is placed in a capsule. In otherembodiments, the composition, in the form of microtablets, is placed ina capsule. The capsule can contain, for example, from about 30microtablets to about 60 microtablets, from about 35 microtablets toabout 55 microtablets, from about 30 to about 50 microtabletes or fromabout 40 microtablets to about 50 microtablets (e.g., about 44, about45, about 46, about 47, or about 48 microtablets).

The dosage form can be administered, for example, once, twice, thrice,four time, five times, or six times per day. One or more dosage form canbe administered, for example, for one, two, three, four, five, six, orseven days. One or more dosage forms can be administered, for example,for one, two, three, or four weeks. One or more dosage forms can beadministered, for example, for one, two, three, four, five, six, seven,eight, nine, ten, eleven, twelve months or longer. One or more dosageforms can be administered until the subject in need thereof does notrequire treatment, prophylaxis, or amelioration of any disease orcondition such as, for example, multiple sclerosis.

In some embodiments, a method described herein comprises orallyadministering a dosage form that provides a total amount of about 60 mgto about 1000 mg of dimethyl fumarate daily. The dosage form can, forexample, contain a total amount of DMF effective for treatment,prophylaxis, or amelioration of multiple sclerosis in a subject. Thedaily effective amount can range, but is not limited to, a total amountof about 60 mg to about 800 mg DMF, about 60 mg to about 720 mg DMF, 60mg to about 500 mg DMF, about 60 mg to about 480 mg DMF, about 60 mg toabout 420 mg DMF, about 60 mg to about 360 mg DMF, about 60 mg to about240 mg DMF, about 60 mg to about 220 mg DMF, about 60 mg to about 200 mgDMF, about 60 mg to about 180 mg DMF, about 60 mg to about 160 mg DMF,about 60 mg to about 140 mg DMF, about 60 mg to about 120 mg DMF, about60 mg to about 100 mg DMF, about 60 mg to about 80 mg DMF, about 80 mgto about 480 mg DMF, about 100 mg to about 480 mg DMF, about 120 mg toabout 480 mg DMF, about 140 mg to about 480 mg DMF, about 160 mg toabout 480 mg DMF, about 180 mg to about 480 mg DMF, about 200 mg toabout 480 mg DMF, about 220 mg to about 480 mg DMF, about 240 mg toabout 480 mg DMF, about 300 mg to about 480 mg DMF, about 360 mg toabout 480 mg DMF, about 400 mg to about 480 mg DMF, about 450 mg toabout 500 mg DMF, about 480 mg to about 500 mg DMF, about 80 to about400 mg DMF, about 100 to about 300 mg DMF, about 120 to about 180 mgDMF, or about 140 mg to about 160 mg DMF.

The dosage form can contain, but is not limited to, a total amount ofDMF of about 60 mg DMF, about 80 mg DMF, about 100 mg DMF, about 120 mgDMF, about 140 mg DMF, about 160 mg DMF, about 180 mg DMF, about 200 mgDMF, about 220 mg DMF, about 240 mg DMF, about 260 mg DMF, about 280 mgDMF, about 300 mg DMF, about 320 mg DMF, about 340 mg DMF, about 360 mgDMF, about 380 mg DMF, about 400 mg DMF, about 420 mg DMF, about 450 mgDMF, about 480 mg DMF, about 500 mg DMF, about 520 mg DMF, about 540 mgDMF, about 560 mg DMF, about 580 mg DMF, about 600 mg DMF, about 620 mgDMF, about 640 mg DMF, about 660 mg DMF, about 680 mg DMF, about 700 mgDMF, about 720 mg DMF, about 740 mg DMF, about 760 mg DMF, about 780 mgDMF or about 800 mg DMF.

In some embodiments, DMF is the only active ingredient in thepharmaceutical composition. In one embodiment, the pharmaceuticalcomposition consists essentially of DMF.

For the treatment of multiple sclerosis (e.g., relapsing forms ofmultiple sclerosis such as RR-MS), the dosage form administered to thesubject can be a capsule with microtablets containing DMF as the onlyactive ingredient or microtablets consisting essentially of DMF, whereinthe effective amount is about 480 mg DMF per day, and the subjects canreceive the effective amount, i.e., 240 mg DMF BID, in the form of twocapsules a day, to be taken orally. For the treatment of multiplesclerosis (e.g., relapsing forms of multiple sclerosis such as RR-MS),the dosage form administered to the subject can be a capsule withmicrotablets containing DMF as the only active ingredient ormicrotablets consisting essentially of DMF, wherein the effective amountis about 720 mg DMF per day, and the subjects can receive the effectiveamount, i.e., 240 mg DMF TID, in the form of three capsules a day, to betaken orally. In one embodiment, the therapeutically effective amount is240 mg twice daily.

In a specific embodiment of the methods described herein, the fumarateis DMF and the dose of DMF is 120 mg DMF BID administered orally for thefirst 7 days. In certain embodiments, the dose is increased to themaintenance dose of 240 mg DMF BID (i.e., 480 mg DMF per day)administered orally. In another embodiment, the dose is increased to 240mg DMF TID (i.e., 720 mg DMF per day) administered orally. In oneembodiment, the administering is of 120 mg twice daily for 7 days,followed by 240 mg twice daily as a maintenance dose.

In a specific embodiment, the fumarate is DMF, and the dose of DMF is120 mg DMF BID administered orally for at least 7 days, followed by amaintenance dose of 240 mg DMF BID administered orally.

In a specific embodiment, the fumarate is DMF, and the dose of DMF is240 mg DMF BID administered orally.

DMF is known to cause flushing and gastrointestinal (GI) side effects incertain subjects. While the side effects generally subside soon aftersubjects start on the treatment, in a specific embodiment, the startingdose is 120 mg DMF BID orally for the first 7 days. The dose can beincreased to 240 mg DMF BID (i.e., 480 mg DMF per day). In otherembodiments, the dose can be increased to 240 mg DMF TID (i.e., 720 mgDMF per day). In certain embodiments, the fumarate is administered withfood. In other embodiments, the fumarate is administered without food.For those subjects who experience GI or flushing side effects,administering a fumarate, for example, DMF, with food improvestolerability. In one embodiment, administering a fumarate, such as DMF,with food reduces the incidence of flushing.

In a specific embodiment, a NSAID (e.g., aspirin) is administeredconcurrently, before, and/or after administration of the fumarate (e.g.,DMF). In a healthy volunteer study, administration of 325 mg non-entericcoated aspirin 30 minutes prior to DMF dosing is found to reduce theoccurrence and severity of flushing in the participating subjects. Somesubjects who experience flushing with gastrointestinal side effects mayreduce the dose to 120 mg DMF BID temporarily. Within a month, theeffective dose of 240 mg DMF BID or 240 mg DMF TID should be resumed.

In one embodiment, subjects administered a dosage form described abovemay take one or more non-steroidal anti-inflammatory drugs (e.g.,aspirin) before (for example, 10 minutes to an hour, e.g., 30 minutesbefore) taking the dosage form described above. In one embodiment, thesubject administered the dosage form takes the one or more non-steroidalanti-inflammatory drugs (e.g., aspirin) to reduce flushing. In anotherembodiment, the one or more non-steroidal anti-inflammatory drugs isselected from a group consisting of aspirin, ibuprofen, naproxen,ketoprofen, celecoxib, and combinations thereof. The one or morenon-steroidal anti-inflammatory drugs can be administered in an amountof about 50 mg to about 500 mg before taking the dosage form describedabove. In one embodiment, a subject takes 325 mg aspirin before takingeach dosage form described above.

In some embodiments, subjects orally administered one or morenon-steroidal anti-inflammatory drugs (e.g., aspirin) before taking thedosage form described above exhibit the same pharmacokinetic properties(e.g., C_(max) and AUC) as subjects orally administered the dosage formdescribed above without administering one or more non-steroidalanti-inflammatory drugs (e.g., aspirin).

In one embodiment, subjects with multiple sclerosis are administered acapsule containing 240 mg DMF, twice daily for a total daily dose of 480mg, wherein the capsule contains multiple microtablets comprising about43% w/w to about 95% w/w (e.g., from about 50% to about 80% w/w) DMF, byweight of the microtablets without any coatings. In another embodiment,subjects having multiple sclerosis are administered a capsule containing240 mg DMF, thrice daily for a total daily dose of 720 mg, wherein thecapsule contains multiple microtablets comprising about 43% w/w to about95% w/w (e.g., from about 50% to about 80% w/w) DMF, by weight of themicrotablets without any coatings. In one embodiment, the microtabletsare first coated with a seal coat and then coated with an enteric coat.In one embodiment, the subjects administered the capsular dosage formexhibit one or more of the pharmacokinetic parameters described above.

5.4 Progressive Multifocal Leukoencephalopathy (PML)

Progressive multifocal leukoencephalopathy (PML) is an opportunisticbrain infection caused by the JC virus (JCV). PML occurs primarily inimmunocompromised individuals and in patients receiving certainimmunomodulatory therapies, including natalizumab. PML is hypothesizedto be the result of a complex interaction between host and viralfactors, leading to reactivation and mutation of latent archetype JCV toa neurotrophic form which can infect oligodendrocytes in the centralnervous system.

In a specific embodiment, the invention provides for monitoring patientsand withholding treatment with a fumarate described herein, such asdimethyl fumarate (e.g., TECFIDERA®), at the first sign or symptomsuggestive of PML, and optionally performing an appropriate diagnosticevaluation.

5.4.1 Monitoring a sign or symptom suggestive of PML

In specific embodiments, the invention provides for monitoring a MSpatient that is being treated with a fumarate for the first sign orsymptom suggestive of PML. Typical symptoms associated with PML arediverse and progress over days to weeks. Sign or symptoms suggestive ofPML include, but are not limited to the following typical symptoms:progressive weakness on one side of the body, clumsiness of limbs,disturbance of vision, and changes in thinking, memory, and orientationleading to confusion and personality changes. Mental function, speech,and movement may also be affected. Additional symptoms may includeataxia, loss of cognitive function, visual loss, changes in balance andcoordination, and loss of sensation. The progression of deficits usuallyleads to death or severe disability over weeks or months.

Unlike multiple sclerosis, in PML involvement of the spinal cord oroptic nerves rarely occurs. Instead, about one-third of patients havevisual field loss or cortical blindness, while another third will showaltered mentation or behavior changes (Dworkin et al., Curr. Clin. Top.Infect. Dis., 2002, 22:181-195). Also unlike multiple sclerosis,hemiparesis is a common symptom. These symptoms are typically sub-acuteat onset, and slowly progress. Often, patients and their families arethe first to notice the onset of PML through changes in the ability toperform routine activities of daily living, even before changes onneurological examination (see WO 2007/100770 at paragraph [094]).

In certain embodiments, a patient with multiple sclerosis who is beingtreated with a fumarate is monitored for a sign or symptom suggestive ofPML in the patient.

In certain embodiments, the treatment with the fumarate is withheld fromthe patient at the first sign or symptom suggestive of PML in thepatient.

In one embodiment, the methods provided herein further compriseperforming a diagnostic evaluation for PML in the patient at the firstsign or symptom suggestive of PML in the patient.

5.4.2 Performing Diagnostic Evaluation for PML

In specific embodiments, the invention provides performing a diagnosticevaluation for PML in the patient at the first sign or symptomsuggestive of PML in the patient. The diagnostic evaluation can be byany method known in the art, including but not limited to magneticresonance imaging (MRI), detection of JC viral DNA in the cerebrospinalfluid (CSF), detection of consistent white matter lesions by MRI,assessing the progressive course of disease, or a combination of any ofthe foregoing.

In a specific embodiment, PML is diagnosed based on a combination of (1)detection of JC viral DNA in CSF; (2) consistent white matter lesionsshown by MM, and optionally (3) progressive course of the disease.

As described in WO 2007/100770, the pathology of PML is distinctive,involving foci of demyelination of varying size from pinpoint lesions toareas of several centimeters. Lesions generally appear in the cerebralhemispheres, less often in the cerebellum and brain stem and rarely inthe spinal cord, although they can appear elsewhere. Theoligodendrocytes in the peripheral zone surrounding an area ofdemyelination appear grossly abnormal. The nuclei of these abnormaloligodendrocytes contain many JC virions.

Certain clinical features of PML help distinguish it from thedemyelination associated with multiple sclerosis.

5.4.2.1. Magnetic Resonance Imaging (MM)

Magnetic Resonance Imaging (MM) can be used to diagnose PML. As shown inTable 1, there are features of PML lesions that help differentiate themfrom other etiologies (Post et al., Am. J. Neuroradiol., 1999,20(10):1896-1906; Yousry et al., N. Engl. J. Med., 2006, 354(9):924-933;Berger et al., Ann. Neural., 1998, 44(3):341-349; Hoffmann et al., J.Neural. Neurosurg. Psychiatry, 2003, 74(8):1142-1144; Langer-Gould etal., N Engl. J. Med., 2005, 353(4):375-381).

In a specific embodiment, the diagnostic evaluation for PML in a patientinvolves detection of consistent white matter lesions by MM.

TABLE 1 Differential Diagnosis of multiple sclerosis and PML (as takenfrom WO 2007/100770 at pp 29-30) Multiple Sclerosis PML Location of newMostly focal, may affect entire Diffuse, mainly sub-cortical, rarelylesions brain and spinal cord, in white and periventricular, almostexclusively possibly gray matter; in white matter, although occasionalPosterior fossa lesions rarely seen extension to gray matter seen;Posterior fossa frequently involved (cerebellum) Borders Sharp edges,shapes mostly round Ill-defined edges, infiltrating, or finger-like(especially irregular in shape, confined to white periventricular),confluent with matter, sparing gray matter, pushing other singlelesions, U-fibers may against cortex, U-fibers destroyed be involvedMode of extension Focal, enlarging of lesions within Diffuse,asymmetrical, extending days/weeks, later decreasing in sizehomogeneously, no confluence with within months other lesions, definedto white matter tracks, sparing cortex, continuous progression Masseffect Acute lesions may show some mass No mass effect even in largelesions effect (but process is slightly pushing against cortex)T2-weighted Acute lesions: hyperintense center, Diffuse hyperintense,slightly sequence isointense ring, discrete increased intensity of newlyhyperintensity outside ring involved areas compared to old structure;areas, little irregular signal intensity Sub-acute/chronic lesions: oflesions hyperintense no ring structure T1-weighted Acute lesions:densely hypointense Slightly hypointense from the onset, sequence (largelesion) or isointense (small signal intensity decreasing over lesion),increasing signal intensity time and along the affected area, no overtime in 80% decreasing signal reversion of signal intensity intensity(axonal loss) in about 20% Flair sequence Hyperintense, sharplydelineated Hyperintensity more obvious, true extension of abnormalitymore clearly visible than in T2-weighted images Enhancement Acutelesions: dense homogeneous Usually no enhancement even in enhancement,sharp edges large lesions, in HIV+ patients some Sub-acute lesions:ring- peripheral enhancement possible, enhancement especially undertherapy Chronic lesions: no enhancement Atrophy Focal atrophy possibledue to focal No focal atrophy since extending white matter degeneration,no pathological process is slightly progression pushing against cortex(extension of tissue)

5.4.2.2. Histological and Virological Examination

In a specific embodiment, the diagnostic evaluation comprises a test forthe presence of JC viral DNA in the CSF of the patient. PCR analysis ofthe cerebrospinal fluid (CSF) for JC viral DNA is a highly sensitive andspecific test for the diagnosis of PML. The specificity of this testapproaches 100%, with a sensitivity ranging from 60% to 90% (Henson etal., Neurology, 1991, 41(12):1967-1971; Gibson et al., J. Med. Virol.,1993, 39(4):278-281; Weber et al., AIDS, 1994, 8(1):49-57; Weber et al.,J. Infect. Dis., 1994, 169(5):1138-1141; Vago et al., J. Acquir. Imm.Defic. Syndr. Hum. Retrovirol., 1996, 12(2):139-146). In cases with ahigh clinical suspicion of PML and negative CSF results, repeat testingoften leads to detection of JC viral DNA. Thus, PCR analysis of the CSFfor JC viral DNA is a useful method for diagnosing PML.

In one embodiment, the diagnostic evaluation further comprises a testfor the presence in the patient of antibodies to JCV. In one aspect, thediagnostic evaluation for PML in the patient involves evaluating thelevel of anti-JCV antibody in a biological sample from the patient. Ingeneral, antibodies to JCV in the blood of patients treated with afumarate may be indicative of risk of future PML, but are not themselvesdiagnostic of PML.

In one aspect, the diagnostic evaluation for PML in the patient involvesevaluating a patient's risk of developing PML by a method comprising atest for the presence in the patient of antibodies to JCV. In oneaspect, the diagnostic evaluation for PML in the patient involvesevaluating a patient's risk of developing PML by a method comprising atest evaluating the level of anti-JCV antibody in a biological samplefrom the patient.

A wide variety of serological tests are available to detect JCV, e.g.,complementfixation (CFT), haemagglutination-inhibition (HA1),enzyme-linked immunoassay (EIA), radioimmunoassay (RIA), particleagglutination, immunofluorescence (IF), single radial hemolysis, andWestern blot. The sensitivity and specificity varies greatly betweendifferent techniques. Most techniques will detect all classes ofantibody, whereas some assays e.g., RIA, EIA, and IF can be designed todetect one specific class, for example, IgM, IgG, or IgA.

In certain embodiments, the patient is tested for JCV in the patient'surine, blood, and/or cerebrospinal fluid (CSF). In a specificembodiment, the testing comprises serially removing samples of thepatient's blood, measuring the amount of IgG antibodies to JCV in thesamples, and comparing the amount of the antibodies in the samples overtime. In other specific embodiments, the testing includes measuring theamount of IgM antibodies to JCV in the samples, and comparing the amountof IgM and IgG antibodies in the samples.

In certain embodiments, the testing detects seroconversion and/or anincreasing titer of JCV in the patient's urine and/or blood, and furtherincludes removing a sample of the patient's cerebrospinal fluid when thecomparison of the serial urine and/or blood samples detectseroconversion and/or an increasing titer of JCV; and testing thecerebrospinal fluid for the presence of JCV antibodies.

In one embodiment, the diagnostic evaluation comprises testing forclinical and/or radiologic symptoms of PML. In certain embodiments, thetesting for clinical symptoms comprises testing for new or worseningneurological symptoms. In specific embodiments, the neurologicalsymptoms comprise one or more of central blindness, mental confusion,personality change, and dyskinesia. In other embodiments, the testingfor radiologic symptoms of PML comprises performing a Gd-enhancedmagnetic resonance imaging scan.

In one embodiment, testing tests for JCV in the patient's urine, blood,and/or cerebrospinal fluid. In a specific embodiment, the monitoringcomprises serially removing samples of the patient's blood, measuringthe amount of IgG antibodies to JCV in the samples, and comparing theamount of the antibodies in the samples over time. In some embodiments,the testing further comprises measuring the amount of IgM antibodies toJCV in the samples, and comparing the amount of the IgM and IgGantibodies in the samples. In one embodiment, the monitoring detectsseroconversion and/or an increasing titer of JCV in the patient's urineand/or blood by removing a sample of the patient's cerebrospinal fluidwhen the comparison of the serial urine and/or blood samples detectseroconversion and/or an increasing titer of JCV; and testing thecerebrospinal fluid for the presence of JCV.

In one aspect, the diagnostic evaluation for PML in the patient involvesevaluating a patient's risk of developing PML by a method comprisingdetermining a JCV antibody titer in a biological sample from thepatient, wherein the patient has a negative prior immunosuppressantexposure classification; wherein if the titer is determined to be abovea pre-determined level, e.g., above an index level of 0.7, 0.8, 0.9,1.0, 1.1, 1.2, 1.3, 1.4, or 1.5, the patient is determined to be at ahigher risk of developing PML, and wherein if the titer is determined tobe at or below a pre-determined level, e.g., at or below an index levelof 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, or 0.7, the patient isdetermined to be at a lower risk of developing PML.

In one aspect, the diagnostic evaluation for PML in the patient involvesevaluating a patient's risk of developing PML by a method comprisingdetermining a JCV antibody titer in two or more biological samplesobtained from the patient over a period of time (e.g., 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or moremonths); wherein if the titer is determined to be above zero, but at orbelow a pre-determined level, e.g., at or below an index level of 1.5,1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, or 0.7, in the two or more samples,the patient is determined to be at a lower risk of developing PML, andwherein if the titer is determined to be above a pre-determined level,e.g., above an index level of 0.7, 0.8, 0.9. 1.0, 1.1, 1.2, 1.3, 1.4, or1.5, in the two or more samples, the patient is determined to be at ahigher risk of developing PML.

In one aspect, the diagnostic evaluation for PML in the patient involvesdetermining a patient's risk of developing PML by a method comprisingevaluating the level of anti-JCV antibody in a biological sample. Themethod comprises one or more or all of the following steps (see WO2012/166971):

(a) forming a first reaction mixture comprising a first aliquot ofsample and a substrate on which is disposed HPVLP (Highly PurifiedVirus-Like Particle consisting predominantly of the JCV major capsidprotein VP1);

(b) detecting the level of anti-JCV antibody bound to said substrate onwhich is disposed HPVLP, e.g., by detecting a labeled detection reagent,e.g., an enzyme labeled anti-IgG antibody, bound to anti-JCV antibodybound to said substrate; thereby evaluating the level of anti-JCVantibody in a sample (the method can comprise classifying, or assigning,to the sample, a value indicative of the level of anti-JCV antibody,which can be used in embodiments, to determine whether to proceed to anadditional step of the method, e.g., step (c) below); and

(c) forming a second reaction mixture containing a second aliquot ofsample and solution-phase HPVLP, and detecting the level of unboundanti-JCV antibody in said second reaction mixture, such as by detectinganti-JCV antibody capable of binding with a substrate on which isdisposed HPVLP (the method can comprise classifying, or assigning, tothe sample, a value indicative of the degree to which incubation withthe soluble-phase HPVLP reduces the level of unbound anti-JCV antibodyin the second reaction mixture, which value can be referred to asinhibition, % inhibition, or the like), thereby evaluating the level ofanti-JCV antibody in the sample.

In an embodiment, the method further comprises (see WO 2012/166971): (d)forming a third reaction mixture containing a third aliquot underconditions where anti-JCV antibodies in the sample are not bound byHPVLP or other antigen, and detecting the level of anti-JCV antibody inthe third reaction mixture, such as by detecting anti-JCV antibodycapable of binding with a substrate on which is disposed HPVLP. Theinhibition or % inhibition can be calculated as a function of the degreethat incubation with soluble-phase HPVLP (step (c)) reduces the amountof unbound anti-JCV antibody, as compared to the result in step (d).

In one aspect, the diagnostic evaluation for PML in the patient involvesa method of evaluating a patient's risk of developing PML, the methodcomprising:

-   -   determining a JC Virus (JCV) antibody titer expressed as nOD,        index or other unit, or other characteristics such as affinity        or avidity expressed as percent inhibition in the anti-JCV        antibody confirmation assay in a biological sample from the        patient, and comparing the titer or/and percent inhibition, or        function of both values, to a pre-determined level.

In one embodiment, a method of evaluating a patient's risk of developingPML further includes testing the serum or plasma of the sample for bothIgG and IgM antibodies to JCV and initiating treatment with a fumarateif the serum or plasma is negative for both IgG and IgM antibodies toJCV.

5.4.3 Treating PML

The cellular receptor for JCV has been reported to be the serotonin5-HT_(2A) receptor (Elphick et al., Science, 2004, 306(5700):1380-1383).It has also been suggested that the 5HT2 antagonist mirtazapine may beuseful in the prophylaxis or treatment of PML (Verma et al., J InfectDis., 2007, 196(5):709-711).

Hexadecyloxypropyl-Cidofovir (CMX001) has also been studied as atreatment option for JCV (Gosert et al., Antimicrob. Agents Chemother.,2011, 55(5):2129-2136) because of its ability to suppress JVC byinhibiting viral DNA replication.

Mefloquine has been reported to block JCV replication withoutsignificant toxicity, and at concentrations achievable in the centralnervous system. Although cases of successful PML treatment withmefloquine in HIV and non-HIV infected patients have been reported(e.g., Young et al., Ann. Acad. Med. Singap., 2012, 41(12):620-624),unsuccessful cases of mefloquine use for treatment of PML have also beenreported (Clifford et al., J. Neurovirol., 2013, 19:351-358; Tyler etal., J. Neurovirol., 2013, 19(4):311-313).

In accordance with the methods provided herein, when the diagnosticevaluation for PML indicates PML in the patient or an elevated risk ofthe patient for developing PML, a method of the invention can furthercomprise administering a therapeutic to the patient for the treatment orprevention of PML. Such therapeutic can be any therapeutic known in theart. Currently, there is no established drug treatment for PML. However,various medications have been tested, including acyclovir, idoxuridine,vidarabine, amantadine, adenine arabinoside, cytosine arabinoside(cytarabine, also known as ARA-C), cidofovir, interferon a,interleukin-2 (IL-2), zidovudine, camptothecin, topotecan, mefloquine,and mirtazapine (Koralnik, Curr. Opt. Neurol., 2004, 17(3):365-370;Dworkin et al., Curr. Clin. Top. Infect. Dis., 2002, 22:181-195; Seth etal., J. Neurovirol., 2003, 9(2):236-246; Collazos, CNS Drugs, 2003,17(12):869-887; Mamidi et al., J. Neurovirol., 2002, 8(3):158-167;Przepiorka et al., Bone Marrow Transplant, 1997, 20(11):983-987;Redington et al., Arch. Neural., 2002, 59(5):712-718; Padgett et al.,Prog. Clin. Biol. Res., 1983, 105:107-117). Thus, in a specificembodiment, such a therapeutic can be HAART, acyclovir, idoxuridine,vidarabine, amantadine, adenine arabinoside, cytosine arabinoside(cytarabine, also known as ARA-C), cidofovir, interferon a,interleukin-2 (IL-2), zidovudine, camptothecin, topotecan,chlorpromazine, clozapine. zisprasidone, risperidone, olanzapine,hexadecyloxypropyl-Cidofovir (CMX001), mefloquine, or mirtazapine.

In one embodiment, the methods provided herein include, when adiagnostic evaluation indicates the presence of PML, providing at leastone treatment of PML selected from intravenous immunoglobulin therapy,plasmapheresis, and antiviral therapy. In certain embodiments, theantiviral therapy comprises the administration of at least onetherapeutically effective dose of an antiviral agent selected fromcytosine arabinoside (cytarabine), cidofovir, and a serotoninantagonist.

Provided herein is a method of using a fumarate described herein totreat a patient with multiple sclerosis by removing a sample of bloodfrom the patient; testing the serum or plasma of the sample for thepresence of IgG antibodies to JCV; initiating treatment of the patientwith the fumarate in the event the sample is negative for IgG antibodiesto JCV; monitoring the patient for signs or symptoms of progressivemultifocal leukoencephalopathy; and discontinuing the administration ofthe fumarate in the presence of signs or symptoms of PML.

In one aspect, an entity, e.g., a healthcare provider, acquiresinformation resulting from an anti-JCV antibody assay described herein,and responsive to the information, administers a treatment describedherein to the patient.

In another aspect, a JCV assay described herein is performed on apatient, and then the patient is treated based on the results of theassay. Thus, for example, if the assay is negative for JCV, treatmentwith a fumarate continues or is initiated, or re-initiated (if fumaratehas been withheld at the first sign or symptom of PML)

5.5 Complete Blood Count

In specific embodiments, the invention provides for obtaining a completeblood count (CBC) including lymphocyte count after 6 months of repeatedadministering of a pharmaceutical composition described herein (e.g.,TECFIDERA®) to a MS patient, and every 6 to 12 months thereafter. In oneembodiment, the administering of the pharmaceutical composition (e.g.,TECFIDERA®) is interrupted when the patient has a lymphocyte count lessthan 0.5×10⁹/L persisting for more than six months. In a specificembodiment, the invention provides for measuring of lymphocyte count inthe patient until lymphopenia is resolved in the patient.

A CBC, also known as a complete blood cell count, full blood count(FBC), or full blood exam (FBE), is a blood test. A CBC providesinformation about the three general types of cells circulating in thebloodstream: white blood cells (leukocytes), red blood cells(erythrocytes), and platelets (thrombocytes). A CBC measures red bloodcells, white blood cells, hemoglobin, hematocrit, and platelets.Evaluation of white blood cells in a CBC panel may include a white bloodcell count, which is the total number of white blood cells in a person'ssample of blood, and may also include white blood cell differential,which identifies and counts the various types of white blood cells suchas lymphocytes, monocytes, neutrophils, eosinophils, and basophils.Evaluation of red blood cells in a CBC panel may include a total redblood cell count, hemoglobin, hematocrit, mean corpuscular volume (MCV),mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobinconcentration (MCHC), red blood cell distribution width (RDW), andreticulocyte count. Platelet evaluation in a CBC test may includeplatelet count, mean platelet volume (MPV), and platelet distributionwidth (PDW). Abnormally high or low counts of a particular type of cellin the bloodstream may indicate the presence of an underlying medicalcondition.

A CBC can be conducted by using methods well known in the art, which maycomprise collecting the blood sample through venipuncture, drawing theblood into a test tube containing an anticoagulant, and counting theblood cells using manual techniques or an automated analyzer (see, e.g.,Buttarello and Plebani, Am. J. Clin. Pathol., 2008, 130(1):104-116).

In controlled and uncontrolled clinical trials of TECFIDERA®, 2% ofpatients experienced lymphocyte counts less than 0.5×10⁹/L for at leastsix months. In these patients, the majority of lymphocyte countsremained less than 0.5×10⁹/L with continued therapy.

5.6 Patient Populations

As used herein, the terms “patient” and “subject” can be usedinterchangeably. The fumarate as described herein is administered to asubject in need thereof, a subject having MS. In a specific embodiment,said subject has been diagnosed as having MS by a medical practitioner.

In some embodiments, the form of the multiple sclerosis is relapsingremitting, secondary progressive, primary progressive, or chronicprogressive multiple sclerosis. In one embodiment, the patient withmultiple sclerosis is a patient with a relapsing form of MS. In aspecific embodiment, the patient has relapse-remitting MS (RR-MS). Inanother specific embodiment, the patient has secondary-progressive MS(SP-MS). In yet another specific embodiment, the patient hasprogressive-relapsing MS (PR-MS).

In one embodiment, the patient is not pregnant. In another embodiment,the patient is not a nursing mother.

In one embodiment, the patient has no hypersensitivity to a fumarate,such as dimethyl fumarate, administered in the methods described herein.In a further embodiment, the patient has no hypersensitivity to thefumarate, such as dimethyl fumarate, or does not know about hishypersensitivity to the fumarate.

In one embodiment, the patient is not treated simultaneously with bothone or more fumarates (e.g., dimethyl fumarate) and anyimmunosuppressive or antineoplastic medication. In certain embodiments,the patient is not treated simultaneously with a fumarate (e.g.,dimethyl fumarate) and any immunosuppressive or immunomodulatorymedications or natalizumab. In certain embodiments, the patient is nottreated simultaneously with a fumarate described herein (e.g., dimethylfumarate) and any medications carrying a known risk of causingprogressive multifocal leukoencephalopathy (PML).

In one embodiment, the patient has never been treated with a fumarate,e.g., dimethyl fumarate, prior to commencement of therapy in accordancewith the methods disclosed herein. In another embodiment, the patienthas not been treated with a fumarate, e.g., dimethyl fumarate, 1, 2, 3,4, 6, 8, 10, or 12 months or 1, 2, 3, 5, 10, 20, 30, 40, or 50 years,prior to commencement of therapy in accordance with the methodsdisclosed herein.

In one embodiment, the patient has never been treated with anyimmunosuppressive or antineoplastic medication prior to commencement oftherapy in accordance with the methods disclosed herein. In a furtherembodiment, the patient has not been treated with any immunosuppressiveor antineoplastic medication 1, 2, 3, 4, 6, 8, 10, or 12 months or 1, 2,3, 5, 10, 20, 30, 40, 50 years, prior to commencement of therapy inaccordance with the methods disclosed herein. In another embodiment, thepatient has never been treated with any immunosuppressive orimmunomodulatory medications or natalizumab prior to commencement oftherapy in accordance with the methods disclosed herein. In yet anotherembodiment, the patient has not been treated with any immunosuppressiveor immunomodulatory medications or natalizumab 1, 2, 3, 4, 6, 8, 10, or12 months or 1, 2, 3, 5, 10, 20, 30, 40, or 50 years, prior tocommencement of therapy in accordance with the methods disclosed herein.In another embodiment, the patient has never been treated with anymedications carrying a known risk of causing PML prior to commencementof therapy in accordance with the methods disclosed herein. In yetanother embodiment, the patient has not been treated with anymedications carrying a know risk of causing PML 1, 2, 3, 4, 6, 8, 10, or12 months or 1, 2, 3, 5, 10, 20, 30, 40, or 50 years, prior tocommencement of therapy in accordance with the methods disclosed herein.

In one embodiment, the immunosuppressive or antineoplastic medication isselected from one or more of: chlorambucil, melphalan, 6-mercaptopurine,thiotepa, ifodfamide, dacarbazine, procarbazine, temozolomide,hexamethylmelamine, doxorubicine, daunarubicine, idarubicin, epirubicin,irinotecan, methotrexate, etoposide, vincristine, vinblastine,vinorelbine, cytarabine, busulfan, amonifide, 5-fluorouracil, topotecan,mustargen, bleomycin, lomustine, semustine, mitomycin C, mutamycin,cisplatin, carboplatin, oxaliplatin, methotrexate, trimetrexate,raltitrexid, flurorodeoxyuridine, capecitabine, ftorafur,5-ethynyluracil, 6-thioguanine, cladribine, pentostatin, teniposide,mitoxantrone, losoxantrone, actinomycin D, vindesine, docetaxel,amifostine, interferon alpha, tamoxefen, edroxyprogesterone, megestrol,raloxifene, letrozole, anastrzole, flutamide, bicalutamide, retinoicacids, arsenic trioxide, rituximab, CAMP ATH-1, mylotarg, mycophenolicacid, tacrolimus, glucocorticoids, sulfasalazine, glatiramer, fumarate,laquinimod, FTY -720, interferon tau, daclizumab, infliximab, IL10,anti-IL2 receptor antibody, anti-IL-12 antibody, anti-IL6 receptorantibody, CDP-571, adalimumab, entaneracept, Ieflunomide,anti-interferon gamma antibody, abatacept, fludarabine,cyclophosphamide, azathioprine, cyclosporine, intravenousimmunoglobulin, 5-ASA (mesalamine), and a (β-interferon.

In one embodiment, the immunosuppressive or immunomodulatory medicationis selected from one or more of: calcinerurin inhibitors,corticosteroids, cytostatics, nitrosoureas, protein synthesisinhibitors, dactinomycin, anthracyclines, mithramycin, polyclonalntibodies such as atgum and thymoglobulin, monoclonal antibodies such asmuromonab-CD3, and basiliximab, ciclosporin, sirolimus, rapamycin,γ-interferon, opioids, TNF binding proteins, TNF-α binding proteins,etanercept, mycophenolate, fingolimode, and myriocin.

In one embodiment, the patient being treated in accordance with themethods described herein has no identified systemic medical conditionresulting in a compromised immune system function.

In one embodiment, the patient has been free of an immunosuppressant orimmunomodulatory therapy for the patient's lifetime, or since diagnosiswith MS, for example a relapsing form of MS.

6. EXAMPLES 6.1 Example 1 Compositions of Dimethyl Fumarate

A pharmaceutical composition comprising dimethyl fumarate was preparedas 2 millimeter enteric coated microtablets in a size 0 hard gelatincapsule. Each capsule contained either 120 mg dimethyl fumarate or 240mg dimethyl fumarate.

6.1.1 Uncoated Core Microtablet Formulations

Dimethyl fumarate (DMF), croscarmellose sodium, talc, and colloidalsilica anhydrous were mixed together to form a blend according to theamounts as described in Table 2. The blend was then passed through ascreen (e.g., screen with 800 micron aperture) and microcrystallinecellulose (PROSOLV SMCC® HD90) was added to the blend and mixed.Magnesium stearate was added to the blend and the blend was remixed. Theresulting blend was then compressed on a suitable rotary tablet pressequipped with 16 multi-tip tooling having 2 mm round concave tips.

Table 2 below provides the weight percentages of ingredients present intwo types of microtablets, 120 mg DMF and 240 mg DMF, respectively, madeusing the method described above. Microtablets were coated as describedin Section 6.1.2 and then loaded into capsules. A size 0 capsulecontaining microtablets made with blend A contains about 120 mg of DMF,whereas the same size capsule containing microtablets made with blend Bcontains about 240 mg of DMF.

TABLE 2 Blend A Blend B, % w/w Com- Per Com- Per position, % microtabletposition, % microtablet Ingredients w/w content (mg) w/w content (mg)DMF 42 3.1 65 5.2 Croscarmellose 5 0.37 5 0.4 sodium Prosolv — — 29 2.3SMCC ® HD90 Avicel PH200 44 3.2 — — Magnesium 1.7 0.12 0.5 0.04 StearateTalc 6.6 0.49 — — Silica colloidal 0.86 0.067 0.6 0.048 anhydrous Total100 7.4 100 8

6.1.2 Microtablet Coating Formulations

The microtablets were coated with two coatings; a seal coating, followedby an enteric coating, using the seal coating formulation and entericcoating formulation of Formula A and Formula B as described in Table 3.The seal coating formulation was a solvent-based formulation which usedisopropyl alcohol as a solvent, and the enteric coating formulation wasbased on methyl acrylic acid copolymer dispersion and provided effectiveenteric protection. The enteric coating formulation containedmethacrylic acid copolymer dispersion and talc in addition to anantifoaming agent (simethicone). The coated microtablets were thenloaded into size 0 hard gelatin capsules.

TABLE 3 Coating Formula A, Coating Formula B, Ingredients % w/w % w/wSeal Coating Formulation Methacrylic acid 44.0 51.7 copolymer, Type A²Triethyl citrate 1.1 1.3 Isopropyl alcohol¹ 54.9 47.1 Enteric CoatingFormulation Methacrylic acid 36.9 44.3 copolymer dispersion² Triethylcitrate 2.2 2.6 Talc, micronized 4.6 5.5 Simethicone 0.2 0.2 (30%emulsion) Purified water¹ 59.0 47.3 ¹Ingredients are removed during theprocess ²Methacrylic acid copolymer Type A and methacrylic acidcopolymer dispersion are anionic copolymers comprising methacrylic acidand methacrylate and are the primary substances in various EUDRAGIT ®formulations, which mediate pH-dependent release of compounds.

6.2 Example 2 Formation of Capsules Containing Microtablets

Dimethyl fumarate, croscarmellose sodium, talcum and colloidal siliconanhydrous are mixed together to form a blend according to the amountsdescribed in Table 4 below. The blend is passed through a screen. Asuitable grade of microcrystalline cellulose, for example, PROSOLV SMCC®90 or PROSOLV SMCC® HD90 is added to the blend and mixed. Magnesiumstearate is added to the blend and the blend is remixed.

The blend is then compressed on a suitable rotary tablet press equippedwith multi-tip tooling (e.g., a 16 multi-tip tooling) having 2 mm roundconcave tips. The resulting 2 mm sized microtablets are coated with asolution of methacrylic acid-methyl methacrylate copolymer and triethylcitrate in isopropanol (see amounts in Table 4 below). The coatedmicrotablets are then coated with a second layer of coating consistingof methacrylic acid- ethylacrylate copolymer, polysorbate 80, sodiumlauryl sulfate, triethyl citrate, simethicone, and talcum micronizedsuspended in water (see amounts in Table 4 below).

The desired amount of coated microtablets are encapsulated in a twopiece hard gelatin capsule using a capsule machine. For example, coatedmicrotablets are encapsulated in a capsule such that the amount ofdimethyl fumarate is about 240 mg per capsule.

In Table 4 below, % w/w is based on the total weight of the coatedmicrotablet (e.g., in this table, % w/w includes the weightcontributions of the coatings).

TABLE 4 Net capsule content, % w/w of the capsule components Example No.Ingredients 1 2 3 4 5 6 7 8 9 10 Dimethyl 43.01 72.30 58.40 54.08 83.6073.90 39.50 65.00 33.90 42.00 fumarate Croscarmellose 1.26 0.33 3.724.17 0.46 0.89 4.43 4.00 4.24 3.00 sodium Microcrystalline 41.82 15.9117.31 23.57 7.00 9.42 31.31 13.66 37.18 35.79 Cellulose Magnesium 1.050.25 0.69 0.41 0.26 0.63 1.32 0.40 1.41 0.48 Stearate Silica colloidal1.21 0.22 0.78 0.97 0.43 0.29 0.69 0.40 0.73 0.68 anhydrous Methacrylic1.01 1.27 0.98 1.51 0.11 1.66 1.87 1.21 1.55 1.32 acid methyl acrylatecopolymer Methacrylic 6.23 4.98 11.12 8.97 4.34 8.21 9.93 7.72 9.04 9.98acid ethyl acrylate copolymer Triethyl citrate 1.61 1.74 2.33 2.12 0.971.67 2.31 2.09 2.15 2.32 Talc 2.56 2.81 4.32 3.90 2.65 3.06 8.32 5.309.46 4.12 Simethicone 0.03 0.02 0.03 0.05 0.02 0.03 0.02 0.02 0.06 0.02polysorbate 80 0.15 0.11 0.24 0.20 0.11 0.18 0.22 0.14 0.21 0.21 SodiumLauryl 0.06 0.06 0.08 0.07 0.05 0.06 0.08 0.06 0.06 0.08 sulfate

6.3 Example 3 Formation of Microtablets

Dimethyl fumarate, croscarmellose sodium, talcum and colloidal siliconanhydrous were mixed together to form blends 1, 2, 4, 5, and 6 accordingto the amounts described in Table 5 below. Each blend was passed througha screen. Microcrystalline cellulose (PROSOLV SMCC® HD90) was added tothe blends according to the amounts in Table 5 and mixed. Magnesiumstearate was then added to each blend and the blend was remixed. Eachblend was then compressed on a suitable rotary tablet press equippedwith 16 multi-tip tooling having 2 mm round concave tips.

Blends 3, 7, 8, and 9 can be made using the same method as describedabove.

TABLE 5 Percent w/w Composition of the Core Microtablet Ingredient Blend1 Blend 2 Blend 3 Blend 4 Blend 5 Blend 6 Blend 7 Blend 8 Blend 9Dimethyl fumarate 42.0 42.0 50.0 60.0 65.0 70.0 75.0 85.0 95.0Croscarmellose sodium 5.0 5.0 3.0 5.0 5.0 5.0 1.0 1.0 0.4Microcrystalline 44.0 50.0 43.0 32.0 28.3 23.0 22.0 13.0 4.0 CelluloseMagnesium Stearate 1.7 1.7 0.5 1.7 0.5 1.3 0.4 0.4 0.4 Silica colloidal0.9 1.2 1.5 1.0 1.2 0.9 0.6 0.5 0.5 anhydrous Talc 6.6 — 2.0 — — — 1.0 —— total 100 100 100 100 100 100 100 100 100

6.4 Example 4 Compacts Containing 42% w/w, 60% w/w, and 70% w/w DimethylFumarate and Control Compacts

Dimethyl fumarate, croscarmellose sodium, and silica colloidal anhydrouswere blended together to form a blend. The blend was passed through ascreen. A suitable grade of microcrystalline cellulose was added to thescreened blend and the blend was mixed. A suitable grade ofmicrocrystalline cellulose, is, for example PROSOLV SMCC® 90, having anaverage particle size by laser diffraction of about 60 μm and a bulkdensity ranging from about 0.38 to about 0.50 g/cm³. Magnesium stearatewas added to the mixed blend and remixing was effected.

The respective blended materials were compressed on a suitable rotarypress (e.g., a rotary tablet press) to form compacts (10 mm cylindricalcompacts).

Table 6 provides percentages for representative compacts made by thisprocess.

TABLE 6 Ingredients 42% 60% 70% Dimethyl fumarate 42 60 70Croscarmellose sodium 5.0 5.0 5.0 Microcrystalline Cellulose 50 32 23Magnesium Stearate 1.7 1.7 1.7 Silica colloidal anhydrous 1.2 1.0 0.9

6.5 Example 5

Compositions Containing 65% w/w, 95% w/w, and 99.5% w/w DimethylFumarate

Four DMF-containing blends were prepared according to the method asdescribed in Example 4 above with the amounts as described in Table 7below.

TABLE 7 Composition, % by weight Ingredients Blend 93 Blend 97 Blend 104Blend 108 Dimethyl 65 95 99.5 95 fumarate Prosolv SMCC 28.9 2 — 2 90Croscarmellose 5 2 — 2 Sodium Silica colloidal, 0.6 0.6 — 0.6 anhydrousMagnesium 0.5 0.4 0.5 0.4 stearate Particle size of 14% <250μ 14% <250μ15% <250μ 84% <250μ dimethyl fumarate Flodex (mm) 4 4 4 6 Bulk density0.66 0.66 0.74 0.69 (g/ml) Tapped 0.79 0.78 0.83 0.83 density(g/ml)Compressi- 17 16 17 17 bility, %

6.6 Example 6 Instructing the Patient

By way of example, but not limitation, instructions in a TECFIDERA®label can be as follows:

Warnings and Precautions Progressive Multifocal Leukoencephalopathy

Monitor patients and withhold TECFIDERA® at the first sign or symptomsuggestive of PML and perform an appropriate diagnostic evaluation.Typical symptoms associated with PML are diverse, progress over days toweeks, and include progressive weakness on one side of the body orclumsiness of limbs, disturbance of vision, and changes in thinking,memory, and orientation leading to confusion and personality changes.The progression of deficits usually leads to death or severe disabilityover weeks or months.

Patient Counselling Information Progressive MultifocalLeukoencephalopathy

Inform patients that progressive multifocal leukoencephalopathy (PML)has occurred in a patient who received TECFIDERA®. Instruct the patientof the importance of contacting their doctor if they develop anysymptoms suggestive of PML. Instruct the patient that typical symptomsassociated with PML are diverse, progress over days to weeks, andinclude progressive weakness on one side of the body or clumsiness oflimbs, disturbance of vision, and changes in thinking, memory, andorientation leading to confusion and personality changes. Instruct thepatient that the progression of deficits usually leads to death orsevere disability over weeks or months.

Instruct patients to continue to look for new signs and symptomssuggestive of PML for approximately 6 months following discontinuationof TECFIDERA® [see WARNINGS AND PRECAUTIONS].

6.7 Example 7 Instructing the Patient—Lymphopenia and Lymphocyte Counts

By way of example, but not limitation, instructions in a TECFIDERA®label can be as follows:

Warnings and Precautions Lymphopenia

Before initiating treatment with TECFIDERA®, a CBC including lymphocytecount should be obtained. A CBC including lymphocyte count should alsobe obtained after 6 months of treatment, every 6 to 12 monthsthereafter, and as clinically indicated. Consider interruption ofTECFIDERA® in patients with lymphocyte counts less than 0.5×10⁹/Lpersisting for more than six months. Given the potential for delay inlymphocyte recovery after discontinuation of TECFIDERA®, considerfollowing lymphocyte counts until lymphopenia is resolved. Withholdingtreatment should be considered in patients with serious infections untilthe infection(s) is resolved. Decisions about whether or not to restartTECFIDERA® should be individualized based on clinical circumstances.

Patient Counselling Information Lymphocyte Counts

Inform patients that TECFIDERA® may decrease lymphocyte counts. A bloodtest should be obtained before they start therapy. Blood tests are alsorecommended after 6 months of treatment, every 6 to 12 monthsthereafter, and as clinically indicated.

6.8 Example 8 Characterization of Absolute Lymphocyte Count Profiles InMS Patients Treated With Delayed-Release Dimethyl Fumarate:Considerations for Patient Management

Delayed-release dimethyl fumarate (DMF; also known as gastro-resistantDMF, and as TECFIDERA®) demonstrated robust efficacy on clinical andneuroradiological measures and an acceptable safety profile inrelapsing-remitting multiple sclerosis (RRMS) in clinical trialsincluding a Phase 2b study, the Phase 3 DEFINE and CONFIRM studies, andthe ENDORSE extension study. ¹⁻⁶

In clinical trials, DMF was associated with flushing andgastrointestinal events as well as decreased white blood cell (WBC) andabsolute lymphocyte counts (ALCs).⁷

ALC profiles were characterized in DMF-treated MS patients in thisstudy. Patients at greater risk for developing severe prolongedlymphopenia were identified. The study also evaluated DMF efficacy inpatients with and without lymphopenia.

Objective

The objective of the analysis was to provide practical considerationsfor management of DMF (as TECFIDERA®)-treated MS patients bycharacterizing ALC profiles and examining efficacy in patients with andwithout lymphopenia enrolled in clinical trials (Phase 2b, DEFINE,CONFIRM, and ENDORSE).

Methods Study Design

The Phase 2b study, DEFINE, and CONFIRM were multicenter, randomized,double-blind, placebo-controlled, parallel-group clinical trials of DMFas monotherapy for RRMS.

The Phase 2b study was 12 months in duration, including a 6-monthplacebo-controlled part (Part 1) and a 6-month uncontrolled safetyextension part (Part 2). During Part 1, patients were randomized equallyto DMF 120 mg once daily (QD), 120 mg three times daily (TID), 240 mgTID, or placebo.

DEFINE and CONFIRM were 2 years in duration. Patients were randomizedequally to DMF 240 mg twice daily (BID), 240 mg TID, or matchingplacebo.

CONFIRM also included glatiramer acetate (GA) as a reference comparatorarm.

ENDORSE is a multicenter, parallel-group, dose-blinded extension ofDEFINE/CONFIRM with up to 8 additional years of follow-up.

Patients who received 240 mg DMF BID or TID for up to 2 years in theparent studies remained on the same DMF dosage in ENDORSE.

Patients who received placebo (DEFINE and CONFIRM) or GA (CONFIRM) inthe parent studies were randomized equally to 240 mg DMF BID or TID.

Key Inclusion and Exclusion Criteria

Key inclusion and exclusion criteria for the Phase 2b study, DEFINE, andCONFIRM are summarized in Table 8.

TABLE 8 Key inclusion and exclusion criteria Key inclusion criteria Age18-55 years Diagnosis of RRMS per McDonald criteria⁸ EDSS score of 0-5.0Key exclusion criteria Progressive forms of MS or other significantillness Relapse within 50 days prior to randomization Corticosteroidswithin 30 days (Phase 2b) or 50 days (DEFINE, CONFIRM) prior torandomization Pre-specified abnormal laboratory parameters including WBC<3.5 × 10⁹/L or eosinophils >0.7 × 10³/μL or >0.7 GI/L Prior treatmentwith potent immunosuppressant agents or procedures Prior treatment withMS therapies within predefined washout periods, including interferonbeta, within 3 months prior to randomization; GA, within 3 months priorto randomization (Phase 2b, DEFINE) or at any time (CONFIRM); ornatalizumab, within 6 months prior to randomization Abbreviations: EDSS,Expanded Disability Status Scale; GA, glatiramer acetate; WBC, whiteblood cell.

Hematology

In the Phase 2b study, blood was collected every 4 weeks.

In DEFINE and CONFIRM, blood was collected every 4 weeks for the first 3months and every 12 weeks thereafter, and within 1 month after studywithdrawal or study completion if not continuing in the extension study.

In ENDORSE, blood was collected at baseline and every 12 weeksthereafter

Hematology included hemoglobin, hematocrit, red blood cell count, WBCcount (with differential), and platelet count.

ALCs were graded per Common Terminology Criteria for Adverse Events

(CTCAE; Table 9).⁹

TABLE 9 CTCAE v4.0 grading for ALCs CTC grade 0 CTC grade 1 CTC grade 2CTC grade 3 CTC grade 4 >LLN^(a) <LLN- <0.8-≧0.5 × <0.5-≧0.2 × <0.2 ×10⁹/L ≧0.8 × 10⁹/L 10⁹/L 10⁹/L ALC = absolute lymphocyte count; CTCAE =Common Terminology Criteria for Adverse Events ^(a)Lower limit of normal(LLN) = 0.91 × 10⁹/L

Statistical Analysis

Data from DEFINE and CONFIRM after subjects switched to alternative MStreatment were excluded.

Data from the 6-month uncontrolled safety extension of the Phase 2bstudy were included.

A data cut-off date was used.

RESULTS Patients

The safety population comprised 2513 MS patients, including 1136 treatedwith DMF 240 mg BID, 1249 treated with DMF 240 mg TID, and 128 treatedwith lower doses of DMF (Table 10). Mean (SD) time on study treatmentamounted to 3.1 (2.2) years (Table 10).

A total of 2470 patients had any post-baseline ALC.

TABLE 10 Time on study treatment Total DMF^(a,b) (n = 2513) Time onstudy treatment, mean (SD) years^(c)  3.1 (2.2) Total number ofcumulative patient-years 7249.96 of exposure to study treatment Patientson study treatment for at least, n (%) 3 months 2218 (88) 6 months 2099(84) 1 year 1869 (74) 2 years 1602 (64) 3 years 1377 (55) 4 years 1001(40) 5 years  740 (29) 6 years  270 (11) 7 years  34 (1) SD = standarddeviation ^(a)DMF, delayed-release DMF (also known as gastro-resistantDMF, and as TECFIDERA ®) ^(b)Includes DMF 240 mg BID, DMF 240 mg TID,and lower doses of DMF (120 mg QD or TID) ^(c)Each year comprised 48weeks.

Mean WBC and ALCs Over Time With Continuing DMF Treatment

Mean baseline ALCs were similar across the groups treated with DMF 240mg BID, DMF 240 mg TID, or lower doses of DMF (FIG. 1).

Mean ALCs decreased by approximately 30% during the first year oftreatment, then plateaued, remaining above the lower limit of normal(LLN; 910/mm³) throughout the observation period (FIG. 1).

Incidence of CTC Grade 0-4 Lymphopenia

For the majority of patients, ALCs were within normal limits at all timepoints (CTC grade 0).

The incidence of worst post-baseline CTC grades 0, 1, 2, and 3 or 4 isshown in Table 11.

TABLE 11 Incidence of CTC grades for worst post-baseline ALCs TotalDMF^(a,b) n (%) (n = 2513) CTC grade 0 1533 (61) CTC grade 1 236 (9) CTCgrade 2  528 (21) CTC grade 3 or 4^(c) 173 (7) No post-baseline ALC  43(2) CTC = Common Terminology Criteria ^(a)DMF, delayed-release DMF (alsoknown as gastro-resistant DMF, and as TECFIDERA ®) ^(b)Includes DMF 240mg BID, DMF 240 mg TID, and lower doses of DMF (120 mg QD or TID) ^(c)2patients (<1%) had CTC grade 4

ALC Profiles

ALCs remained greater than or equal to LLN in 84% of patients during thefirst 6 months and in 76% of patients during the first year; of thesepatients, 0.1% and 0%, respectively, developed ALCs less than 500/mm³persisting for greater than or equal to 6 months at any time (Table 12).

Among patients treated for greater than or equal to 6 months (N=2,099),2.2% (n=47) experienced ALCs less than 500/mm³ persisting for greaterthan or equal to 6 months, ALCs generally remained less than 500/mm³with continued therapy.

TABLE 12 Proportion of patients who subsequently developed ALCs <500/mm³persisting ≧6 months at any time (up to 7 years after initiatingtreatment) according to ALCs within the first 6 months or first 1 yearof DMF treatment n/N (%) All ALCs ≧LLN^(b) 3/2083 (0.1) 0/1876 (0) AllALCs ≧800/mm³ 9/2219 (0.4) 0/2050 (0) All ALCs ≧500/mm³ 37/2446 (1.5)  16/2409 (0.7) At least 1 ALC <500/mm³ 38/251 (10)   47/420 (17) Atleast 1 ALC <500/mm³  10/24 (42)  31/61 (51) ALC = absolute lymphocytecount ^(b)Lower limit of normal (LLN) = 0.91 × 10⁹/LTime Course of Mean ALC Changes in Patients with ALCs<500/mm³Persisting≧6 months

Mean ALCs in the subgroup of patients with ALCs less than 500/mm³persisting for greater than or equal to 6 months showed a faster declinecompared with mean counts in the subgroup of patients without less than500/mm³ persisting for greater than or equal to 6 months (FIG. 2).

Recovery of ALCs Post-Discontinuation of DMF Treatment

Among the 47 patients with ALCs less than 500 cells/4, for at least 6months, 9 patients discontinued or completed the study. Of the 9patients, 8 had ALCs measured at least 1 month after their final dose.All 9 patients showed increases in ALCs following their final dose ofDMF (FIG. 3). The remaining 38 patients remained on treatment at thetime of this analysis; however, a protocol amendment for ENDORSE wentinto effect six months later and stipulated that study treatment must betemporarily withheld if ALC is less than 500/mm³ for more than 6 months.While dosing is withheld, patients will be followed every 4 weeks untilthe ALC is greater than or equal to LLN or for 24 weeks after the lastdose (whichever is sooner). If ALC remains to be less than 500/mm³ for24 weeks after the last dose, then study treatment must be permanentlydiscontinued.

Efficacy in Patients with Lymphopenia (<LLN) Versus Patients WithoutLymphopenia

Reduction in annualized relapse rate (ARR) at 2 years in patientstreated with DMF 240 mg BID versus placebo was not substantiallydifferent in patients with lymphopenia (at least 1 ALC less than LLN)versus patients without lymphopenia (all ALCs greater than LLN) inDEFINE and CONFIRM (FIGS. 4A-4B). In DEFINE (FIG. 4A), the rate ratio(95% CI) for adjusted ARR for DMF versus placebo was 0.424 (0.294,0.611) and 0.509 (0.381, 0.681) in patients with and withouttreatment-associated lymphopenia, respectively. In CONFIRM (FIG. 4B),the rate ratio (95% CI) for adjusted ARR for DMF versus placebo was0.525 (0.365, 0.756) and 0.599 (0.429, 0.835) in patients with andwithout treatment-associated lymphopenia, respectively.

Baseline characteristics including EDSS score, age, region, and numberof relapses in the 1 year prior to study entry were similar across theplacebo and DMF groups in patients with or without lymphopenia.

General Safety

As identified in this interim analysis of the Phase 2b, DEFINE, CONFIRM,and ENDORSE clinical studies, lymphopenia in DMF-treated patients wasnot associated with an overall increased risk of infections or seriousinfections, including opportunistic infections (Table 13). Subsequent tothe data cut-off for this interim report, a case of PML in a patienttreated with DMF 240 mg TID was reported in the setting of severe,prolonged lymphopenia (approximately less than 0.5×10⁹/L of 3.5 yearsduration).

TABLE 13 Incidence of serious infections by worst post-baseline CTCgrade Total DMF^(a,b) Serious infections,^(c) n (%) (n = 2513) CTC grade0 43 (3) CTC grade 1   13 (5.5) CTC grade 2 22 (4) CTC grade 3 or 4  5(3) ALC, absolute lymphocyte count; CTC, Common Terminology Criteria.^(a)DMF, delayed-release DMF (also known as gastro-resistant DMF, and asTECFIDERA ®) ^(b)Includes DMF 240 mg BID, DMF 240 mg TID, and lowerdoses of DMF (120 mg QD or TID) ^(c)For each CTC grade, numbers inparentheses are percentages based on the number with an infection out ofthe number with worst post-baseline count in that grade as shown inTable 11.

Conclusions

ALC profiles are well characterized and stable over time. Mean ALCsdecreased by approximately 30% in DMF-treated patients during the firstyear of treatment, then plateaued, remaining above LLN throughout theobservation period.

ALCs remained greater than or equal to LLN in 84% of patients during thefirst 6 months and in 76% of patients during the first year; of thesepatients, 0.1% and 0%, respectively, developed ALCs less than 500/mm³persisting for greater than or equal to 6 months at any time.

Among patients treated for at least 6 months, a small proportion (2.2%)experienced ALCs less than 500/mm³ persisting for greater than or equalto 6 months and this finding was an early predictor for those patientsat greater risk for subsequently developing severe, prolongedlymphopenia.

Aside from a single case of PML in the setting of severe, prolongedlymphopenia, there is no overall increased risk for serious infections,including other opportunistic infections.

Before initiating treatment with DMF, a recent CBC including lymphocytes(i.e., within 6 months) should be available. A CBC including lymphocytesis also recommended after 6 months of treatment, every 6 to 12 monthsthereafter, and as clinically indicated.⁷ As indicated in the productlabelling, consider interruption of DMF in patients with ALCs less than0.5×10⁹/L persisting for more than 6 months. Following interruption ofDMF, ALCs should be followed until lymphopenia is resolved.^(∂).

Although the data are limited, there is evidence of ALC improvementfollowing discontinuation of DMF treatment.

Therapeutic efficacy of DMF both in patients with lymphopenia and inpatients without lymphopenia suggests that lymphopenia is not a primarymechanism of action of DMF. Efficacy in patients with and withoutlymphopenia suggests that lymphopenia is not a primary mechanism ofaction of DMF.

The overall benefit-risk of DMF remains favorable. Together withclinical and neuroradiologic efficacy, these data continue to supportDMF as a valuable long-term treatment option for patients with RRMS.

References for Example 8

-   -   1. Kappos L, Gold R, Miller D H, et al. Lancet 2008;        372:1463-1472.    -   2. Gold R, Kappos L, Arnold D L, et al. N Engl J Med 2012;        367:1098-1107.    -   3. Fox R J, Miller D H, Phillips J T, et al. N Engl J Med 2012;        367:1087-1097.    -   4. Gold R, Phillips J T, Bar-Or A, et al. Five-year follow-up of        delayed-release dimethyl fumarate in RRMS: integrated clinical        efficacy data from the DEFINE, CONFIRM, and ENDORSE studies.        Poster presented at: Joint ECTRIMS-ACTRIMS Meeting; Sep. 10-13,        2014; Boston Mass. P110.    -   5. Arnold D L, Fox R J, Havrdova E, et al. Five-year follow-up        of delayed-release dimethyl fumarate in relapsing-remitting        multiple sclerosis: Mill outcomes from DEFINE, CONFIRM, and        ENDORSE. Poster presented at: Joint ECTRIMS-ACTRIMS Meeting;        Sep. 10-13, 2014; Boston Mass. P059.    -   6. Pozzilli C, Phillips J T, Fox R J, et al. Long-term follow-up        of the safety of delayed-release dimethyl fumarate in RRMS:        interim results from the ENDORSE extension study. Poster        presented at: Joint ECTRIMS-ACTRIMS Meeting; Sep. 10-13, 2014;        Boston Mass. P066.    -   7. TECFIDERA™ (dimethyl fumarate) [prescribing information].        Biogen Idec. Cambridge, Mass. Rev 12/2014.    -   8. Polman C H, Reingold S C, Edan G, et al. Ann Neurol 2005;        58:840-846.    -   9. National Cancer Institute. Common Terminology Criteria for        Adverse Events v4.0, NCI, NIH, DHHS. May 29, 2009. NIH        publication # 09-7473.

6.9 Example 9 Instructing the Patient—Summary of Product Characteristics

By way of example, but not limitation, instructions for TECFIDERA® usein a Summary of Product Characteristics can be as follows:

Special Warnings and Precautions for Use

Blood/laboratory tests

Changes in renal and hepatic laboratory tests have been seen in clinicaltrials in subjects treated with TECFIDERA®. The clinical implications ofthese changes are unknown. Assessments of renal function (e.g.creatinine, blood urea nitrogen and urinalysis) and hepatic function(e.g. ALT and AST) are recommended prior to treatment initiation, after3 and 6 months of treatment, every 6 to 12 months thereafter and asclinically indicated.

TECFIDERA® may decrease lymphocyte counts. TECFIDERA® has not beenstudied in patients with pre-existing low lymphocyte counts and cautionshould be exercised when treating these patients. Prior to initiatingtreatment with TECFIDERA®, a current complete blood count, includinglymphocytes, must be performed. If lymphocyte count is found to be belowthe normal range, alternative causes of lymphopenia should be consideredand corrective measures taken as appropriate. After starting therapy,complete blood counts, including lymphocytes, must be performed every 3months. Treatment should be discontinued if lymphocyte count<0.7×10⁹/Lis confirmed on repeat testing (at 3 months). Lymphocyte counts shouldbe followed until recovery.

Progressive Multifocal Leukoencephalopathy (PML)

PML cases have occurred with TECFIDERA® in the setting of severe andprolonged lymphopenia. PML is an opportunistic infection caused byJohn-Cunningham virus (JCV), which may be fatal or result in severedisability. PML is likely caused by a combination of factors. Riskfactors include an altered or weakened immune system and potentiallyfurther genetic or environmental risk factors.

Patients with lymphocyte counts<0.5×10⁹/L were observed in<1% ofpatients treated with placebo and 6% of patients treated withTECFIDERA®. In clinical studies (both controlled and uncontrolled), 2%of patients experienced lymphocyte counts<0.5×10⁹/L for at least sixmonths. In these patients, the majority of lymphocyte countsremained<0.5×10⁹/L with continued therapy.

If therapy is continued in presence of severe prolonged lymphopenia, therisk of an opportunistic infection, including PML cannot be ruled out.Therefore patients who experience lymphopenia should be monitoredclosely for signs and symptoms of appearance of new neurologicaldysfunction (e.g. motor dysfunction, cognitive or psychiatric symptoms).In case PML is suspected, treatment with TECFIDERA® should be withheldimmediately and further evaluations performed.

Prior Treatment with Immunosuppressive or Immunomodulating Therapies

No controlled clinical studies have been performed evaluating theefficacy and safety of TECFIDERA® when switching patients from otherdisease modifying therapies to TECFIDERA®. The contribution of priorimmunosuppressive therapy to the development of PML in TECFIDERA®treated patients is unknown. When switching patients from anotherdisease modifying therapy to TECFIDERA®, the half-life and mode ofaction of the other therapy must be considered in order to avoid anadditive immune effect whilst at the same time minimising the risk ofdisease reactivation. A complete blood count, including lymphocytes,must be performed prior to initiating TECFIDERA® and regularly duringtreatment (see blood/laboratory tests above).

TECFIDERA® can generally be started immediately after discontinuation ofinterferon or glatiramer acetate.

In accordance with good clinical practice an MRI should be consideredwhen switching between disease modifying therapies.

Severe Renal and Hepatic Impairment

TECFIDERA® has not been studied in patients with severe renal or severehepatic impairment and caution should, therefore, be used in thesepatients.

Severe Active Gastrointestinal Disease

TECFIDERA® has not been studied in patients with severe activegastrointestinal disease and caution should, therefore, be used in thesepatients.

Flushing

In clinical trials, 34% of TECFIDERA® treated patients experiencedflushing. In the majority of patients who experienced flushing, it wasmild or moderate in severity.

In clinical trials, 3 patients out of a total of 2,560 patients treatedwith TECFIDERA® experienced serious flushing symptoms that were probablehypersensitivity or anaphylactoid reactions. These events were notlife-threatening, but led to hospitalisation. Prescribers and patientsshould be alert to this possibility in the event of severe flushingreactions.

Infections

In phase III placebo-controlled studies, the incidence of infections(60% vs 58%) and serious infections (2% vs 2%) was similar in patientstreated with TECFIDERA® or placebo, respectively. There was no increasedincidence of serious infections observed in patients with lymphocytecounts<0.8×10⁹/L or<0.5×10⁹/L. During treatment with TECFIDERA® in theMS placebo controlled trials, mean lymphocyte counts decreased byapproximately 30% from baseline at one year and then plateaued. Meanlymphocyte counts remained within normal limits. Patients withlymphocyte counts<0.5×10⁹/L were observed in<1% of patients treated withplacebo and 6% of patients treated with TECFIDERA® . In clinical studies(both controlled and uncontrolled), 2% of patients experiencedlymphocyte counts<0.5×10⁹/L for at least six months. In these patients,the majority of lymphocyte counts remained<0.5×10⁹/L with continuedtherapy.

If therapy is continued in presence of severe prolonged lymphopenia, therisk of an opportunistic infection, including Progressive MultifocalLeukoencephalopathy (PML) cannot be ruled out (please refer tosubsection PML above for further details).

If a patient develops a serious infection, suspending treatment withTECFIDERA® should be considered and the benefits and risks should bereassessed prior to re-initiation of therapy. Patients receivingTECFIDERA® should be instructed to report symptoms of infections to aphysician. Patients with serious infections should not start treatmentwith TECFIDERA® until the infection(s) is resolved.

6.10 Example 10 Instructing the Patient—Package Leaflet

By way of example, but not limitation, instructions for TECFIDERA® usein a Package Leaflet can be as follows:

Warnings and Precautions

TECFIDERA® may affect your white blood cell counts, your kidneys andliver. Before you start TECFIDERA®, your doctor will do a blood test tocount the number of your white blood cells and will check that yourkidneys and liver are working properly. Your doctor will test theseperiodically during treatment. If your number of white blood cellsdecreases during treatment, your doctor may consider stopping yourtreatment.

7. INCORPORATION BY REFERENCE

Various references such as patents, patent applications, andpublications are cited herein, the disclosures of which are herebyincorporated by reference herein in their entireties.

What is claimed is:
 1. A method of treating a patient with multiplesclerosis comprising (a) administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that a fumarate salt is not present in thepharmaceutical composition; and (b) monitoring the patient for a sign orsymptom suggestive of progressive multifocal leukoencephalopathy(hereinafter “PML”) in the patient.
 2. A method of improving safety intreatment of a patient with multiple sclerosis comprising monitoring apatient with multiple sclerosis who is being treated with apharmaceutical composition comprising a fumarate for a sign or symptomsuggestive of PML in the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that a fumarate salt is not present in thepharmaceutical composition.
 3. The method of claim 1 or claim 2 whichfurther comprises withholding treatment with the fumarate from thepatient at the first sign or symptom suggestive of PML in the patient.4. The method of any of claims 1-3 which further comprises performing adiagnostic evaluation for PML in the patient at the first sign orsymptom suggestive of PML in the patient.
 5. The method of claim 4 whichfurther comprises administering a therapeutic to the patient for thetreatment for the treatment of PML when the diagnostic evaluationindicates PML in the patient.
 6. The method of claim 3 which furthercomprises instructing the patient to continue to look for new signs andsymptoms suggestive of PML for approximately 6 months followingdiscontinuation of treatment with the fumarate.
 7. A method of treatinga patient with multiple sclerosis comprising (a) administering apharmaceutical composition comprising a fumarate to the patient; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or a clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing; with the proviso that a fumaratesalt is not present in the pharmaceutical composition; and (b) informingthe patient that PML has occurred in a patient who received dimethylfumarate.
 8. A method of treating a patient with multiple sclerosiscomprising (a) administering a pharmaceutical composition comprising afumarate to the patient; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a clathrate, solvate, tautomer, or stereoisomer of anyof the foregoing, or a combination of any of the foregoing; with theproviso that a fumarate salt is not present in the pharmaceuticalcomposition; and (b) instructing the patient of the importance ofcontacting the patient's doctor if the patient develops any symptomssuggestive of PML.
 9. The method of claim 8 which further comprisesinstructing the patient that typical symptoms associated with PML arediverse, progress over days to weeks, and include progressive weaknesson one side of the body or clumsiness of limbs, disturbance of vision,and changes in thinking, memory, and orientation leading to confusionand personality changes.
 10. The method of claim 9 which furthercomprises instructing the patient that progression of deficitsassociated with PML usually leads to death or severe disability overweeks or months.
 11. A method of improving safety in treatment of apatient with multiple sclerosis comprising informing a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition comprising a fumarate that PML has occurred in a patient whoreceived dimethyl fumarate; wherein the fumarate is a dialkyl fumarate,a monoalkyl fumarate, a combination of a dialkyl fumarate and amonoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that a fumarate salt is not present in thepharmaceutical composition.
 12. A method of improving safety intreatment of a patient with multiple sclerosis comprising instructing apatient with multiple sclerosis who is being treated with apharmaceutical composition comprising a fumarate of the importance ofcontacting the patient's doctor if the patient develops any symptomssuggestive of PML; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a clathrate, solvate, tautomer, or stereoisomer of anyof the foregoing, or a combination of any of the foregoing; with theproviso that a fumarate salt is not present in the pharmaceuticalcomposition.
 13. The method of claim 12 which further comprisesinstructing the patient that typical symptoms associated with PML arediverse, progress over days to weeks, and include progressive weaknesson one side of the body or clumsiness of limbs, disturbance of vision,and changes in thinking, memory, and orientation leading to confusionand personality changes.
 14. The method of claim 13 which furthercomprises instructing the patient that progression of deficitsassociated with PML usually leads to death or severe disability overweeks or months.
 15. The method of claim 4, wherein the diagnosticevaluation comprises a test for the presence of JC viral DNA in thecerebrospinal fluid of the patient.
 16. The method of any of claims 1-6,8, 10, 12, and 15, wherein the sign or symptom suggestive of PML isselected from the group consisting of progressive weakness on one sideof the body or clumsiness of limbs, disturbance of vision, and changesin thinking, memory, and orientation leading to confusion andpersonality changes.
 17. The method of any of claims 1, 7-10, and claimsdependent on any of the foregoing, wherein the administering is doneorally.
 18. The method of any of claims 1-17, wherein the pharmaceuticalcomposition comprises a therapeutically effective amount of the fumarateand a pharmaceutically acceptable carrier.
 19. The method of claim 18,wherein the pharmaceutical composition is in the form of a tablet or acapsule.
 20. The method of claim 18, wherein the pharmaceuticalcomposition is in the form of an enterically coated tablet.
 21. Themethod of claim 18, wherein the pharmaceutical composition is in theform of a capsule containing enterically coated microtablets.
 22. Themethod of any of claims 1-21, wherein the fumarate is dimethyl fumarateand/or monomethyl fumarate.
 23. The method of claim 22, wherein thefumarate is dimethyl fumarate.
 24. The method of claim 17, wherein theadministering is of 240 mg twice daily of dimethyl fumarate.
 25. Themethod of claim 17, wherein the administering is of 120 mg dimethylfumarate twice daily for 7 days, followed by 240 mg dimethyl fumaratetwice daily as a maintenance dose.
 26. The method of claim 17, whereinthe administering is of not greater than 720 mg daily total fumarates.27. The method of claim 17, wherein the administering is of not greaterthan 480 mg daily total fumarates.
 28. The method of any of claims 18and 23-27, wherein the pharmaceutical composition consists essentiallyof dimethyl fumarate.
 29. The method of any of claims 24-28, wherein thepharmaceutical composition is in the form of a tablet or a capsule. 30.The method of any of claims 24-28, wherein the pharmaceuticalcomposition is in the form of an enterically coated tablet.
 31. Themethod of any of claims 24-28, wherein the pharmaceutical composition isin the form of a capsule containing enterically coated microtablets. 32.The method of any of claims 1-31, wherein the multiple sclerosis is arelapsing form of multiple sclerosis.
 33. A method of treating a patientwith multiple sclerosis comprising (a) administering a pharmaceuticalcomposition comprising a fumarate to the patient; wherein the fumarateis a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a pharmaceuticallyacceptable salt, clathrate, solvate, tautomer, or stereoisomer of any ofthe foregoing, or a combination of any of the foregoing; with theproviso that an ethyl hydrogen fumarate salt is not present in thepharmaceutical composition; and (b) monitoring the patient for a sign orsymptom suggestive of PML in the patient.
 34. A method of improvingsafety in treatment of a patient with multiple sclerosis comprisingmonitoring a patient with multiple sclerosis who is being treated with apharmaceutical composition comprising a fumarate for a sign or symptomsuggestive of PML in the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that an ethylhydrogen fumarate salt is not present in the pharmaceutical composition.35. The method of claim 33 or claim 34 which further compriseswithholding treatment with the fumarate from the patient at the firstsign or symptom suggestive of PML in the patient.
 36. The method of anyof claims 33-35 which further comprises performing a diagnosticevaluation for PML in the patient at the first sign or symptomsuggestive of PML in the patient.
 37. The method of claim 36 whichfurther comprises administering a therapeutic to the patient for thetreatment for the treatment of PML when the diagnostic evaluationindicates PML in the patient.
 38. The method of claim 35 which furthercomprises instructing the patient to continue to look for new signs andsymptoms suggestive of PML for approximately 6 months followingdiscontinuation of treatment with the fumarate.
 39. A method of treatinga patient with multiple sclerosis comprising (a) administering apharmaceutical composition comprising a fumarate to the patient; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that an ethyl hydrogen fumarate salt is notpresent in the pharmaceutical composition; and (b) informing the patientthat PML has occurred in a patient who received dimethyl fumarate.
 40. Amethod of treating a patient with multiple sclerosis comprising (a)administering a pharmaceutical composition comprising a fumarate to thepatient; wherein the fumarate is a dialkyl fumarate, a monoalkylfumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate,a prodrug of monoalkyl fumarate, a deuterated form of any of theforegoing, or a pharmaceutically acceptable salt, clathrate, solvate,tautomer, or stereoisomer of any of the foregoing, or a combination ofany of the foregoing; with the proviso that an ethyl hydrogen fumaratesalt is not present in the pharmaceutical composition; and (b)instructing the patient of the importance of contacting the patient'sdoctor if the patient develops any symptoms suggestive of PML.
 41. Themethod of claim 40 which further comprises instructing the patient thattypical symptoms associated with PML are diverse, progress over days toweeks, and include progressive weakness on one side of the body orclumsiness of limbs, disturbance of vision, and changes in thinking,memory, and orientation leading to confusion and personality changes.42. The method of claim 41 which further comprises instructing thepatient that progression of deficits associated with PML usually leadsto death or severe disability over weeks or months.
 43. A method ofimproving safety in treatment of a patient with multiple sclerosiscomprising informing a patient with multiple sclerosis who is beingtreated with a pharmaceutical composition comprising a fumarate that PMLhas occurred in a patient who received dimethyl fumarate; wherein thefumarate is a dialkyl fumarate, a monoalkyl fumarate, a combination of adialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that an ethyl hydrogen fumarate salt is notpresent in the pharmaceutical composition.
 44. A method of improvingsafety in treatment of a patient with multiple sclerosis comprisinginstructing a patient with multiple sclerosis who is being treated witha pharmaceutical composition comprising a fumarate of the importance ofcontacting the patient's doctor if the patient develops any symptomssuggestive of PML; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a pharmaceutically acceptable salt, clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing; with the proviso that an ethylhydrogen fumarate salt is not present in the pharmaceutical composition.45. The method of claim 44 which further comprises instructing thepatient that typical symptoms associated with PML are diverse, progressover days to weeks, and include progressive weakness on one side of thebody or clumsiness of limbs, disturbance of vision, and changes inthinking, memory, and orientation leading to confusion and personalitychanges.
 46. The method of claim 45 which further comprises instructingthe patient that progression of deficits associated with PML usuallyleads to death or severe disability over weeks or months.
 47. The methodof claim 36, wherein the diagnostic evaluation comprises a test for thepresence of JC viral DNA in the cerebrospinal fluid of the patient. 48.The method of any of claims 33-38, 40, 42, 44, and 47, wherein the signor symptom suggestive of PML is selected from the group consisting ofprogressive weakness on one side of the body or clumsiness of limbs,disturbance of vision, and changes in thinking, memory, and orientationleading to confusion and personality changes.
 49. The method of any ofclaims 33, 39-42, and claims dependent on any of the foregoing, whereinthe administering is done orally.
 50. The method of any of claims 33-49,wherein the pharmaceutical composition comprises a therapeuticallyeffective amount of the fumarate and a pharmaceutically acceptablecarrier.
 51. The method of claim 50, wherein the pharmaceuticalcomposition is in the form of a tablet or a capsule.
 52. The method ofclaim 50, wherein the pharmaceutical composition is in the form of anenterically coated tablet.
 53. The method of claim 50, wherein thepharmaceutical composition is in the form of a capsule containingenterically coated microtablets.
 54. The method of any of claims 33-53,wherein the fumarate is dimethyl fumarate and/or monomethyl fumarate.55. The method of claim 54, wherein the fumarate is dimethyl fumarate.56. The method of claim 49, wherein the administering is of 240 mg twicedaily of dimethyl fumarate.
 57. The method of claim 49, wherein theadministering is of 120 mg dimethyl fumarate twice daily for 7 days,followed by 240 mg dimethyl fumarate twice daily as a maintenance dose.58. The method of claim 49, wherein the administering is of not greaterthan 720 mg daily total fumarates.
 59. The method of claim 49, whereinthe administering is of not greater than 480 mg daily total fumarates.60. The method of any of claims 50 and 55-59, wherein the pharmaceuticalcomposition consists essentially of dimethyl fumarate.
 61. The method ofany of claims 56-60, wherein the pharmaceutical composition is in theform of a tablet or a capsule.
 62. The method of any of claims 56-60,wherein the pharmaceutical composition is in the form of an entericallycoated tablet.
 63. The method of any of claims 56-60, wherein thepharmaceutical composition is in the form of a capsule containingenterically coated microtablets.
 64. The method of any of claims 33-63,wherein the multiple sclerosis is a relapsing form of multiplesclerosis.
 65. A method of treating a patient with multiple sclerosiscomprising (a) administering a pharmaceutical composition comprising afumarate to the patient; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a pharmaceutically acceptable salt, clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition; and (b)monitoring the patient for a sign or symptom suggestive of PML in thepatient.
 66. A method of improving safety in treatment of a patient withmultiple sclerosis comprising monitoring a patient with multiplesclerosis who is being treated with a pharmaceutical compositioncomprising a fumarate for a sign or symptom suggestive of PML in thepatient; wherein the fumarate is a dialkyl fumarate, a monoalkylfumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate,a prodrug of monoalkyl fumarate, a deuterated form of any of theforegoing, or a pharmaceutically acceptable salt, clathrate, solvate,tautomer, or stereoisomer of any of the foregoing, or a combination ofany of the foregoing; with the proviso that ethyl hydrogen fumaratecalcium salt, ethyl hydrogen fumarate magnesium salt, ethyl hydrogenfumarate zinc salt, and ethyl hydrogen fumarate copper salt are notpresent in the pharmaceutical composition.
 67. The method of claim 65 orclaim 66 which further comprises withholding treatment with the fumaratefrom the patient at the first sign or symptom suggestive of PML in thepatient.
 68. The method of any of claims 65-67 which further comprisesperforming a diagnostic evaluation for PML in the patient at the firstsign or symptom suggestive of PML in the patient.
 69. The method ofclaim 68 which further comprises administering a therapeutic to thepatient for the treatment for the treatment of PML when the diagnosticevaluation indicates PML in the patient.
 70. The method of claim 67which further comprises instructing the patient to continue to look fornew signs and symptoms suggestive of PML for approximately 6 monthsfollowing discontinuation of treatment with the fumarate.
 71. A methodof treating a patient with multiple sclerosis comprising (a)administering a pharmaceutical composition comprising a fumarate to thepatient; wherein the fumarate is a dialkyl fumarate, a monoalkylfumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate,a prodrug of monoalkyl fumarate, a deuterated form of any of theforegoing, or a pharmaceutically acceptable salt, clathrate, solvate,tautomer, or stereoisomer of any of the foregoing, or a combination ofany of the foregoing; with the proviso that ethyl hydrogen fumaratecalcium salt, ethyl hydrogen fumarate magnesium salt, ethyl hydrogenfumarate zinc salt, and ethyl hydrogen fumarate copper salt are notpresent in the pharmaceutical composition; and (b) informing the patientthat PML has occurred in a patient who received dimethyl fumarate.
 72. Amethod of treating a patient with multiple sclerosis comprising (a)administering a pharmaceutical composition comprising fumarate to thepatient; wherein the fumarate is a dialkyl fumarate, a monoalkylfumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate,a prodrug of monoalkyl fumarate, a deuterated form of any of theforegoing, or a pharmaceutically acceptable salt, clathrate, solvate,tautomer, or stereoisomer of any of the foregoing, or a combination ofany of the foregoing; with the proviso that ethyl hydrogen fumaratecalcium salt, ethyl hydrogen fumarate magnesium salt, ethyl hydrogenfumarate zinc salt, and ethyl hydrogen fumarate copper salt are notpresent in the pharmaceutical composition; and (b) instructing thepatient of the importance of contacting the patient's doctor if thepatient develops any symptoms suggestive of PML.
 73. The method of claim72 which further comprises instructing the patient that typical symptomsassociated with PML are diverse, progress over days to weeks, andinclude progressive weakness on one side of the body or clumsiness oflimbs, disturbance of vision, and changes in thinking, memory, andorientation leading to confusion and personality changes.
 74. The methodof claim 73 which further comprises instructing the patient thatprogression of deficits associated with PML usually leads to death orsevere disability over weeks or months.
 75. A method of improving safetyin treatment of a patient with multiple sclerosis comprising informing apatient with multiple sclerosis who is being treated with apharmaceutical composition comprising a fumarate that PML has occurredin a patient who received dimethyl fumarate; wherein the fumarate is adialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a pharmaceuticallyacceptable salt, clathrate, solvate, tautomer, or stereoisomer of any ofthe foregoing, or a combination of any of the foregoing; with theproviso that ethyl hydrogen fumarate calcium salt, ethyl hydrogenfumarate magnesium salt, ethyl hydrogen fumarate zinc salt, and ethylhydrogen fumarate copper salt are not present in the pharmaceuticalcomposition.
 76. A method of improving safety in treatment of a patientwith multiple sclerosis comprising instructing a patient with multiplesclerosis who is being treated with a pharmaceutical compositioncomprising a fumarate of the importance of contacting the patient'sdoctor if the patient develops any symptoms suggestive of PML; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that ethyl hydrogen fumarate calcium salt,ethyl hydrogen fumarate magnesium salt, ethyl hydrogen fumarate zincsalt, and ethyl hydrogen fumarate copper salt are not present in thepharmaceutical composition.
 77. The method of claim 76 which furthercomprises instructing the patient that typical symptoms associated withPML are diverse, progress over days to weeks, and include progressiveweakness on one side of the body or clumsiness of limbs, disturbance ofvision, and changes in thinking, memory, and orientation leading toconfusion and personality changes.
 78. The method of claim 77 whichfurther comprises instructing the patient that progression of deficitsassociated with PML usually leads to death or severe disability overweeks or months.
 79. The method of claim 68, wherein the diagnosticevaluation comprises a test for the presence of JC viral DNA in thecerebrospinal fluid of the patient.
 80. The method of any of claims65-70, 72, 74, 76, and 79, wherein the sign or symptom suggestive of PMLis selected from the group consisting of progressive weakness on oneside of the body or clumsiness of limbs, disturbance of vision, andchanges in thinking, memory, and orientation leading to confusion andpersonality changes.
 81. The method of any of claims 65, 71-74, andclaims dependent on any of the foregoing, wherein the administering isdone orally.
 82. The method of any of claims 65-81, wherein thepharmaceutical composition comprises a therapeutically effective amountof the fumarate and a pharmaceutically acceptable carrier.
 83. Themethod of claim 82, wherein the pharmaceutical composition is in theform of a tablet or a capsule.
 84. The method of claim 82, wherein thepharmaceutical composition is in the form of an enterically coatedtablet.
 85. The method of claim 82, wherein the pharmaceuticalcomposition is in the form of a capsule containing enterically coatedmicrotablets.
 86. The method of any of claims 65-85, wherein thefumarate is dimethyl fumarate and/or monomethyl fumarate.
 87. The methodof claim 86, wherein the fumarate is dimethyl fumarate.
 88. The methodof claim 81, wherein the administering is of 240 mg twice daily ofdimethyl fumarate.
 89. The method of claim 81, wherein the administeringis of 120 mg dimethyl fumarate twice daily for 7 days, followed by 240mg dimethyl fumarate twice daily as a maintenance dose.
 90. The methodof claim 81, wherein the administering is of not greater than 720 mgdaily total fumarates.
 91. The method of claim 81, wherein theadministering is of not greater than 480 mg daily total fumarates. 92.The method of any of claims 82 and 87-91, wherein the pharmaceuticalcomposition consists essentially of dimethyl fumarate.
 93. The method ofany of claims 88-92, wherein the pharmaceutical composition is in theform of a tablet or a capsule.
 94. The method of any of claims 88-92,wherein the pharmaceutical composition is in the form of an entericallycoated tablet.
 95. The method of any of claims 88-92, wherein thepharmaceutical composition is in the form of a capsule containingenterically coated microtablets.
 96. The method of any of claims 65-95,wherein the multiple sclerosis is a relapsing form of multiplesclerosis.
 97. A method of treating a patient with multiple sclerosiscomprising p1 (a) administering a pharmaceutical composition consistingessentially of dimethyl fumarate and/or monomethyl fumarate to thepatient; and (b) monitoring the patient for a sign or symptom suggestiveof PML in the patient.
 98. A method of improving safety in treatment ofa patient with multiple sclerosis comprising monitoring a patient withmultiple sclerosis who is being treated with a pharmaceuticalcomposition consisting essentially of dimethyl fumarate and/ormonomethyl fumarate for a sign or symptom suggestive of PML in thepatient.
 99. The method of claim 97 or claim 98 which further compriseswithholding treatment with the pharmaceutical composition from thepatient at the first sign or symptom suggestive of PML in the patient.100. The method of any of claims 97-99 which further comprisesperforming a diagnostic evaluation for PML in the patient at the firstsign or symptom suggestive of PML in the patient.
 101. The method ofclaim 100 which further comprises administering a therapeutic to thepatient for the treatment for the treatment of PML when the diagnosticevaluation indicates PML in the patient.
 102. The method of claim 99which further comprises instructing the patient to continue to look fornew signs and symptoms suggestive of PML for approximately 6 monthsfollowing discontinuation of treatment with the pharmaceuticalcomposition.
 103. A method of treating a patient with multiple sclerosiscomprising (a) administering a pharmaceutical composition consistingessentially of dimethyl fumarate and/or monomethyl fumarate to thepatient; and (b) informing the patient that PML has occurred in apatient who received dimethyl fumarate.
 104. A method of treating apatient with multiple sclerosis comprising (a) administering apharmaceutical composition consisting essentially of dimethyl fumarateand/or monomethyl fumarate to the patient; and (b) instructing thepatient of the importance of contacting the patient's doctor if thepatient develops any symptoms suggestive of PML.
 105. The method ofclaim 104 which further comprises instructing the patient that typicalsymptoms associated with PML are diverse, progress over days to weeks,and include progressive weakness on one side of the body or clumsinessof limbs, disturbance of vision, and changes in thinking, memory, andorientation leading to confusion and personality changes.
 106. Themethod of claim 105 which further comprises instructing the patient thatprogression of deficits associated with PML usually leads to death orsevere disability over weeks or months.
 107. A method of improvingsafety in treatment of a patient with multiple sclerosis comprisinginforming a patient with multiple sclerosis who is being treated with apharmaceutical composition consisting essentially of dimethyl fumarateand/or monomethyl fumarate that PML has occurred in a patient whoreceived dimethyl fumarate.
 108. A method of improving safety intreatment of a patient with multiple sclerosis comprising instructing apatient with multiple sclerosis who is being treated with apharmaceutical composition consisting essentially of dimethyl fumarateand/or monomethyl fumarate of the importance of contacting the patient'sdoctor if the patient develops any symptoms suggestive of PML.
 109. Themethod of claim 108 which further comprises instructing the patient thattypical symptoms associated with PML are diverse, progress over days toweeks, and include progressive weakness on one side of the body orclumsiness of limbs, disturbance of vision, and changes in thinking,memory, and orientation leading to confusion and personality changes.110. The method of claim 109 which further comprises instructing thepatient that progression of deficits associated with PML usually leadsto death or severe disability over weeks or months.
 111. The method ofclaim 100, wherein the diagnostic evaluation comprises a test for thepresence of JC viral DNA in the cerebrospinal fluid of the patient. 112.The method of any of claims 97-102, 104, 106, 108, and 111, wherein thesign or symptom suggestive of PML is selected from the group consistingof progressive weakness on one side of the body or clumsiness of limbs,disturbance of vision, and changes in thinking, memory, and orientationleading to confusion and personality changes.
 113. The method of any ofclaims 97, 103-106, and claims dependent on any of the foregoing,wherein the administering is done orally.
 114. The method of any ofclaims 97-113, wherein the pharmaceutical composition comprises apharmaceutically acceptable carrier.
 115. The method of claim 114,wherein the pharmaceutical composition is in the form of a tablet or acapsule.
 116. The method of claim 114, wherein the pharmaceuticalcomposition is in the form of an enterically coated tablet.
 117. Themethod of claim 114, wherein the pharmaceutical composition is in theform of a capsule containing enterically coated microtablets.
 118. Themethod of any of claims 97-117, wherein the pharmaceutical compositionconsists essentially of dimethyl fumarate.
 119. The method of claim 113,wherein the administering is of 240 mg twice daily of dimethyl fumarate.120. The method of claim 113, wherein the administering is of 120 mgdimethyl fumarate twice daily for 7 days, followed by 240 mg dimethylfumarate twice daily as a maintenance dose.
 121. The method of claim 119or 120, wherein the pharmaceutical composition consists essentially ofdimethyl fumarate.
 122. The method of claim 113, wherein theadministering is of not greater than 720 mg daily total fumarates. 123.The method of claim 113, wherein the administering is of not greaterthan 480 mg daily total fumarates.
 124. The method of claim 113, whereinthe pharmaceutical composition consists essentially of dimethylfumarate, and the administering is of not greater than 720 mg dailydimethyl fumarate.
 125. The method of claim 113, wherein thepharmaceutical composition consists essentially of dimethyl fumarate,and the administering is of not greater than 480 mg daily dimethylfumarate.
 126. The method of any of claims 119-125, wherein thepharmaceutical composition is in the form of a tablet or a capsule. 127.The method of any of claims 119-125, wherein the pharmaceuticalcomposition is in the form of an enterically coated tablet.
 128. Themethod of any of claims 119-125, wherein the pharmaceutical compositionis in the form of a capsule containing enterically coated microtablets.129. The method of any of claims 97-128, wherein the multiple sclerosisis a relapsing form of multiple sclerosis.
 130. A method of treating apatient with multiple sclerosis comprising (a) administering apharmaceutical composition comprising a fumarate to the patient; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or a clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing; with the proviso that a fumaratesalt is not present in the pharmaceutical composition; and (b) obtaininga complete blood count including lymphocyte count after 6 months ofrepeated administering of said pharmaceutical composition to saidpatient, and every 6 to 12 months thereafter.
 131. The method of claim130, which further comprises interrupting administering of saidpharmaceutical composition to said patient when the patient has alymphocyte count less than 0.5×10⁹/L persisting for more than sixmonths.
 132. The method of claim 131, which further comprises measuringlymphocyte count in said patient until lymphopenia is resolved in saidpatient.
 133. The method of any of claims 130-132, wherein theadministering is done orally.
 134. The method of any of claims 130-133,wherein the pharmaceutical composition comprises a therapeuticallyeffective amount of the fumarate and a pharmaceutically acceptablecarrier.
 135. The method of claim 134, wherein the pharmaceuticalcomposition is in the form of a tablet or a capsule.
 136. The method ofclaim 134, wherein the pharmaceutical composition is in the form of anenterically coated tablet.
 137. The method of claim 134, wherein thepharmaceutical composition is in the form of a capsule containingenterically coated microtablets.
 138. The method of any of claims130-137, wherein the fumarate is dimethyl fumarate and/or monomethylfumarate.
 139. The method of claim 138, wherein the fumarate is dimethylfumarate.
 140. The method of claim 133, wherein the administering is of240 mg twice daily of dimethyl fumarate.
 141. The method of claim 133,wherein the administering is of 120 mg dimethyl fumarate twice daily for7 days, followed by 240 mg dimethyl fumarate twice daily as amaintenance dose.
 142. The method of claim 133, wherein theadministering is of not greater than 720 mg daily total fumarates. 143.The method of claim 133, wherein the administering is of not greaterthan 480 mg daily total fumarates.
 144. The method of any of claims 134and 139-143, wherein the pharmaceutical composition consists essentiallyof dimethyl fumarate.
 145. The method of any of claims 140-144, whereinthe pharmaceutical composition is in the form of a tablet or a capsule.146. The method of any of claims 140-144, wherein the pharmaceuticalcomposition is in the form of an enterically coated tablet.
 147. Themethod of any of claims 140-144, wherein the pharmaceutical compositionis in the form of a capsule containing enterically coated microtablets.148. The method of any of claims 130-147, wherein the multiple sclerosisis a relapsing form of multiple sclerosis.
 149. A method of treating apatient with multiple sclerosis comprising (a) administering apharmaceutical composition comprising a fumarate to the patient; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that an ethyl hydrogen fumarate salt is notpresent in the pharmaceutical composition; and (b) obtaining a completeblood count including lymphocyte count after 6 months of repeatedadministering of said pharmaceutical composition to said patient, andevery 6 to 12 months thereafter.
 150. The method of claim 149, whichfurther comprises interrupting administering of said pharmaceuticalcomposition to said patient when the patient has a lymphocyte count lessthan 0.5×10⁹/L persisting for more than six months.
 151. The method ofclaim 150, which further comprises measuring lymphocyte count in saidpatient until lymphopenia is resolved in said patient.
 152. The methodof any of claims 149-151, wherein the administering is done orally. 153.The method of any of claims 149-152, wherein the pharmaceuticalcomposition comprises a therapeutically effective amount of the fumarateand a pharmaceutically acceptable carrier.
 154. The method of claim 153,wherein the pharmaceutical composition is in the form of a tablet or acapsule.
 155. The method of claim 153, wherein the pharmaceuticalcomposition is in the form of an enterically coated tablet.
 156. Themethod of claim 153, wherein the pharmaceutical composition is in theform of a capsule containing enterically coated microtablets.
 157. Themethod of any of claims 149-156, wherein the fumarate is dimethylfumarate and/or monomethyl fumarate.
 158. The method of claim 157,wherein the fumarate is dimethyl fumarate.
 159. The method of claim 152,wherein the administering is of 240 mg twice daily of dimethyl fumarate.160. The method of claim 152, wherein the administering is of 120 mgdimethyl fumarate twice daily for 7 days, followed by 240 mg dimethylfumarate twice daily as a maintenance dose.
 161. The method of claim152, wherein the administering is of not greater than 720 mg daily totalfumarates.
 162. The method of claim 152, wherein the administering is ofnot greater than 480 mg daily total fumarates.
 163. The method of any ofclaims 153 and 158-162, wherein the pharmaceutical composition consistsessentially of dimethyl fumarate.
 164. The method of any of claims159-163, wherein the pharmaceutical composition is in the form of atablet or a capsule.
 165. The method of any of claims 159-163, whereinthe pharmaceutical composition is in the form of an enterically coatedtablet.
 166. The method of any of claims 159-163, wherein thepharmaceutical composition is in the form of a capsule containingenterically coated microtablets.
 167. The method of any of claims149-166, wherein the multiple sclerosis is a relapsing form of multiplesclerosis.
 168. A method of treating a patient with multiple sclerosiscomprising (a) administering a pharmaceutical composition comprising afumarate to the patient; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a pharmaceutically acceptable salt, clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition; and (b)obtaining a complete blood count including lymphocyte count after 6months of repeated administering of said pharmaceutical composition tosaid patient, and every 6 to 12 months thereafter.
 169. The method ofclaim 168, which further comprises interrupting administering of saidpharmaceutical composition to said patient when the patient has alymphocyte count less than 0.5×10⁹/L persisting for more than sixmonths.
 170. The method of claim 169, which further comprises measuringlymphocyte count in said patient until lymphopenia is resolved in saidpatient.
 171. The method of any of claims 168-170, wherein theadministering is done orally.
 172. The method of any of claims 168-171,wherein the pharmaceutical composition comprises a therapeuticallyeffective amount of the fumarate and a pharmaceutically acceptablecarrier.
 173. The method of claim 172, wherein the pharmaceuticalcomposition is in the form of a tablet or a capsule.
 174. The method ofclaim 172, wherein the pharmaceutical composition is in the form of anenterically coated tablet.
 175. The method of claim 172, wherein thepharmaceutical composition is in the form of a capsule containingenterically coated microtablets.
 176. The method of any of claims168-175, wherein the fumarate is dimethyl fumarate and/or monomethylfumarate.
 177. The method of claim 176, wherein the fumarate is dimethylfumarate.
 178. The method of claim 171, wherein the administering is of240 mg twice daily of dimethyl fumarate.
 179. The method of claim 171,wherein the administering is of 120 mg dimethyl fumarate twice daily for7 days, followed by 240 mg dimethyl fumarate twice daily as amaintenance dose.
 180. The method of claim 171, wherein theadministering is of not greater than 720 mg daily total fumarates. 181.The method of claim 171, wherein the administering is of not greaterthan 480 mg daily total fumarates.
 182. The method of any of claims 172and 177-181, wherein the pharmaceutical composition consists essentiallyof dimethyl fumarate.
 183. The method of any of claims 178-182, whereinthe pharmaceutical composition is in the form of a tablet or a capsule.184. The method of any of claims 178-182, wherein the pharmaceuticalcomposition is in the form of an enterically coated tablet.
 185. Themethod of any of claims 178-182, wherein the pharmaceutical compositionis in the form of a capsule containing enterically coated microtablets.186. The method of any of claims 168-185, wherein the multiple sclerosisis a relapsing form of multiple sclerosis.
 187. A method of treating apatient with multiple sclerosis comprising (a) administering apharmaceutical composition consisting essentially of dimethyl fumarateand/or monomethyl fumarate to the patient; and (b) obtaining a completeblood count including lymphocyte count after 6 months of repeatedadministering of said pharmaceutical composition to said patient, andevery 6 to 12 months thereafter.
 188. The method of claim 187, whichfurther comprises interrupting administering of said pharmaceuticalcomposition to said patient when the patient has a lymphocyte count lessthan 0.5×10⁹/L persisting for more than six months.
 189. The method ofclaim 188, which further comprises measuring lymphocyte count in saidpatient until lymphopenia is resolved in said patient.
 190. The methodof any of claims 187-189, wherein the administering is done orally. 191.The method of any of claims 187-190, wherein the pharmaceuticalcomposition comprises a therapeutically effective amount of the fumarateand a pharmaceutically acceptable carrier.
 192. The method of claim 191,wherein the pharmaceutical composition is in the form of a tablet or acapsule.
 193. The method of claim 191, wherein the pharmaceuticalcomposition is in the form of an enterically coated tablet.
 194. Themethod of claim 191, wherein the pharmaceutical composition is in theform of a capsule containing enterically coated microtablets.
 195. Themethod of any of claims 187-194, wherein the fumarate is dimethylfumarate and/or monomethyl fumarate.
 196. The method of claim 195,wherein the fumarate is dimethyl fumarate.
 197. The method of claim 190,wherein the administering is of 240 mg twice daily of dimethyl fumarate.198. The method of claim 190, wherein the administering is of 120 mgdimethyl fumarate twice daily for 7 days, followed by 240 mg dimethylfumarate twice daily as a maintenance dose.
 199. The method of claim190, wherein the administering is of not greater than 720 mg daily totalfumarates.
 200. The method of claim 190, wherein the administering is ofnot greater than 480 mg daily total fumarates.
 201. The method of any ofclaims 191 and 196-200, wherein the pharmaceutical composition consistsessentially of dimethyl fumarate.
 202. The method of any of claims197-201, wherein the pharmaceutical composition is in the form of atablet or a capsule.
 203. The method of any of claims 197-201, whereinthe pharmaceutical composition is in the form of an enterically coatedtablet.
 204. The method of any of claims 197-201, wherein thepharmaceutical composition is in the form of a capsule containingenterically coated microtablets.
 205. The method of any of claims187-204, wherein the multiple sclerosis is a relapsing form of multiplesclerosis.
 206. A method of treating a patient with multiple sclerosiscomprising: (a) prior to initiating treatment of the patient with apharmaceutical composition comprising a fumarate: (i) performing acomplete blood count including lymphocyte count; and (ii) if thelymphocyte count is found to be below the normal range, consideringalternative causes of lymphopenia, and taking corrective measures asappropriate regarding said alternative causes; and (b) administeringsaid pharmaceutical composition to the patient, wherein the fumarate isa dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a clathrate, solvate,tautomer, or stereoisomer of any of the foregoing, or a combination ofany of the foregoing; with the proviso that a fumarate salt is notpresent in the pharmaceutical composition.
 207. A method of treating apatient with multiple sclerosis comprising: (a) repeatedly administeringa pharmaceutical composition comprising a fumarate to the patient;wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, acombination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug ofmonoalkyl fumarate, a deuterated form of any of the foregoing, or aclathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that afumarate salt is not present in the pharmaceutical composition; and (b)obtaining a complete blood count including lymphocyte count every 3months after starting therapy of said patient with said pharmaceuticalcomposition.
 208. The method of claim 207, which further comprisesdiscontinuing administering of said pharmaceutical composition to saidpatient when the patient has a lymphocyte count less than 0.7×10⁹/L thatis confirmed on repeat testing after 3 months.
 209. A method of treatinga patient with multiple sclerosis comprising (a) administering apharmaceutical composition comprising a fumarate to the patient; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or a clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing; with the proviso that a fumaratesalt is not present in the pharmaceutical composition; and (b)monitoring the patient closely for signs or symptoms of appearance ofnew neurological dysfunction if the patient experiences lymphopeniaafter administering of said pharmaceutical composition.
 210. A method ofimproving safety in treatment of a patient with multiple sclerosiscomprising monitoring a patient with multiple sclerosis who is beingtreated with a pharmaceutical composition comprising a fumarate, and whoexperiences lymphopenia, for signs or symptoms of appearance of newneurological dysfunction; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a clathrate, solvate, tautomer, or stereoisomer of anyof the foregoing, or a combination of any of the foregoing; with theproviso that a fumarate salt is not present in the pharmaceuticalcomposition.
 211. The method of claim 209 or 210 wherein the signs orsymptoms comprise motor dysfunction and cognitive or psychiatricsymptoms.
 212. The method of any one of claims 209-211 which furthercomprises: if PML is suspected, withholding treatment with saidpharmaceutical composition immediately and performing furtherevaluations.
 213. A method of treating multiple sclerosis in a patientwho is being treated with a multiple sclerosis disease-modifying therapyother than a pharmaceutical composition comprising a fumarate; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or a clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing; with the proviso that a fumaratesalt is not present in the pharmaceutical composition; said methodcomprising the following steps in the stated order: (a) stoppingadministration of said multiple sclerosis disease-modifying therapy tosaid patient; (b) considering the half-life and mode of action of saidmultiple sclerosis disease-modifying therapy in order to avoid anadditive immune effect whilst at the same time minimizing the risk ofdisease reactivation; and (c) administering the pharmaceuticalcomposition comprising the fumarate to the patient.
 214. A method oftreating multiple sclerosis in a patient who is being treated withinterferon or glatiramer acetate, said method comprising: (a)discontinuing administration of interferon or glatiramer acetate to thepatient; and (b) immediately after said discontinuing, startingadministering to the patient of a pharmaceutical composition comprisinga fumarate; wherein the fumarate is a dialkyl fumarate, a monoalkylfumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate,a prodrug of monoalkyl fumarate, a deuterated form of any of theforegoing, or a clathrate, solvate, tautomer, or stereoisomer of any ofthe foregoing, or a combination of any of the foregoing; with theproviso that a fumarate salt is not present in the pharmaceuticalcomposition.
 215. The method of claim 213 or 214, wherein the methodfurther comprises performing an MRI on the patient before said startingadministering to the patient of the pharmaceutical compositioncomprising the fumarate.
 216. A method of treating a patient withmultiple sclerosis comprising: (a) administering a pharmaceuticalcomposition comprising a fumarate to the patient; wherein the fumarateis a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a clathrate, solvate,tautomer, or stereoisomer of any of the foregoing, or a combination ofany of the foregoing; with the proviso that a fumarate salt is notpresent in the pharmaceutical composition; and (b) prior to the initialadministering of the pharmaceutical composition comprising the fumarateto the patient, and periodically during treatment of said patient withsaid pharmaceutical composition comprising the fumarate, having a bloodtest done to count the number of white blood cells in the patient; and(c) considering stopping said treatment with said pharmaceuticalcomposition comprising the fumarate if the number of white blood cellsdecreases during said treatment.
 217. The method of any of claim 206,207, 209, 213, 214, or 216, wherein the administering of saidpharmaceutical composition is done orally.
 218. The method of any ofclaims 206-217, wherein the pharmaceutical composition comprises atherapeutically effective amount of the fumarate and a pharmaceuticallyacceptable carrier.
 219. The method of claim 218, wherein thepharmaceutical composition is in the form of a tablet or a capsule. 220.The method of claim 218, wherein the pharmaceutical composition is inthe form of an enterically coated tablet.
 221. The method of claim 218,wherein the pharmaceutical composition is in the form of a capsulecontaining enterically coated microtablets.
 222. The method of any ofclaims 206-221, wherein the fumarate is dimethyl fumarate and/ormonomethyl fumarate.
 223. The method of claim 222, wherein the fumarateis dimethyl fumarate.
 224. The method of claim 217, wherein theadministering is of 240 mg twice daily of dimethyl fumarate.
 225. Themethod of claim 217, wherein the administering is of 120 mg dimethylfumarate twice daily for 7 days, followed by 240 mg dimethyl fumaratetwice daily as a maintenance dose.
 226. The method of claim 217, whereinthe administering is of not greater than 720 mg daily total fumarates.227. The method of claim 217, wherein the administering is of notgreater than 480 mg daily total fumarates.
 228. The method of any ofclaims 218 and 223-227, wherein the pharmaceutical composition consistsessentially of dimethyl fumarate.
 229. The method of any of claims224-228, wherein the pharmaceutical composition is in the form of atablet or a capsule.
 230. The method of any of claims 224-228, whereinthe pharmaceutical composition is in the form of an enterically coatedtablet.
 231. The method of any of claims 224-228, wherein thepharmaceutical composition is in the form of a capsule containingenterically coated microtablets.
 232. The method of any of claims206-231, wherein the multiple sclerosis is a relapsing form of multiplesclerosis.
 233. A method of treating a patient with multiple sclerosiscomprising: (a) prior to initiating treatment of the patient with apharmaceutical composition comprising a fumarate: (i) performing acomplete blood count including lymphocyte count; and (ii) if thelymphocyte count is found to be below the normal range, consideringalternative causes of lymphopenia, and taking corrective measures asappropriate regarding said alternative causes; and (b) administeringsaid pharmaceutical composition to the patient, wherein the fumarate isa dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a pharmaceuticallyacceptable salt, clathrate, solvate, tautomer, or stereoisomer of any ofthe foregoing, or a combination of any of the foregoing; with theproviso that an ethyl hydrogen fumarate salt is not present in thepharmaceutical composition.
 234. A method of treating a patient withmultiple sclerosis comprising: (a) repeatedly administering apharmaceutical composition comprising a fumarate to the patient; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that an ethyl hydrogen fumarate salt is notpresent in the pharmaceutical composition; and (b) obtaining a completeblood count including lymphocyte count every 3 months after startingtherapy of said patient with said pharmaceutical composition.
 235. Themethod of claim 234, which further comprises discontinuing administeringof said pharmaceutical composition to said patient when the patient hasa lymphocyte count less than 0.7×10⁹/L that is confirmed on repeattesting after 3 months.
 236. A method of treating a patient withmultiple sclerosis comprising (a) administering a pharmaceuticalcomposition comprising a fumarate to the patient; wherein the fumarateis a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a pharmaceuticallyacceptable salt, clathrate, solvate, tautomer, or stereoisomer of any ofthe foregoing, or a combination of any of the foregoing; with theproviso that an ethyl hydrogen fumarate salt is not present in thepharmaceutical composition; and (b) monitoring the patient closely forsigns or symptoms of appearance of new neurological dysfunction if thepatient experiences lymphopenia after administering of saidpharmaceutical composition.
 237. A method of improving safety intreatment of a patient with multiple sclerosis comprising monitoring apatient with multiple sclerosis who is being treated with apharmaceutical composition comprising a fumarate, and who experienceslymphopenia, for signs or symptoms of appearance of new neurologicaldysfunction; wherein the fumarate is a dialkyl fumarate, a monoalkylfumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate,a prodrug of monoalkyl fumarate, a deuterated form of any of theforegoing, or a pharmaceutically acceptable salt, clathrate, solvate,tautomer, or stereoisomer of any of the foregoing, or a combination ofany of the foregoing; with the proviso that an ethyl hydrogen fumaratesalt is not present in the pharmaceutical composition.
 238. The methodof claim 236 or 237 wherein the signs or symptoms comprise motordysfunction and cognitive or psychiatric symptoms.
 239. The method ofany one of claims 236-238 which further comprises: if PML is suspected,withholding treatment with said pharmaceutical composition immediatelyand performing further evaluations.
 240. A method of treating multiplesclerosis in a patient who is being treated with a multiple sclerosisdisease-modifying therapy other than a pharmaceutical compositioncomprising a fumarate; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a pharmaceutically acceptable salt, clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing; with the proviso that an ethylhydrogen fumarate salt is not present in the pharmaceutical composition;said method comprising the following steps in the stated order: (a)stopping administration of said multiple sclerosis disease-modifyingtherapy to said patient; (b) considering the half-life and mode ofaction of said multiple sclerosis disease-modifying therapy in order toavoid an additive immune effect whilst at the same time minimizing therisk of disease reactivation; and (c) administering the pharmaceuticalcomposition comprising the fumarate to the patient.
 241. A method oftreating multiple sclerosis in a patient who is being treated withinterferon or glatiramer acetate, said method comprising: (a)discontinuing administration of interferon or glatiramer acetate to thepatient; and (b) immediately after said discontinuing, startingadministering to the patient of a pharmaceutical composition comprisinga fumarate; wherein the fumarate is a dialkyl fumarate, a monoalkylfumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate,a prodrug of monoalkyl fumarate, a deuterated form of any of theforegoing, or a pharmaceutically acceptable salt, clathrate, solvate,tautomer, or stereoisomer of any of the foregoing, or a combination ofany of the foregoing; with the proviso that an ethyl hydrogen fumaratesalt is not present in the pharmaceutical composition.
 242. The methodof claim 240 or 241, wherein the method further comprises performing anMRI on the patient before said starting administering to the patient ofthe pharmaceutical composition comprising the fumarate.
 243. A method oftreating a patient with multiple sclerosis comprising: (a) administeringa pharmaceutical composition comprising a fumarate to the patient;wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, acombination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug ofmonoalkyl fumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that an ethyl hydrogen fumarate salt is notpresent in the pharmaceutical composition; and (b) prior to the initialadministering of the pharmaceutical composition comprising the fumarateto the patient, and periodically during treatment of said patient withsaid pharmaceutical composition comprising the fumarate, having a bloodtest done to count the number of white blood cells in the patient; and(c) considering stopping said treatment with said pharmaceuticalcomposition comprising the fumarate if the number of white blood cellsdecreases during said treatment.
 244. The method of any of claim 233,234, 236, 240, 241, or 243, wherein the administering of saidpharmaceutical composition is done orally.
 245. The method of any ofclaims 233-244, wherein the pharmaceutical composition comprises atherapeutically effective amount of the fumarate and a pharmaceuticallyacceptable carrier.
 246. The method of claim 245, wherein thepharmaceutical composition is in the form of a tablet or a capsule. 247.The method of claim 245, wherein the pharmaceutical composition is inthe form of an enterically coated tablet.
 248. The method of claim 245,wherein the pharmaceutical composition is in the form of a capsulecontaining enterically coated microtablets.
 249. The method of any ofclaims 233-248, wherein the fumarate is dimethyl fumarate and/ormonomethyl fumarate.
 250. The method of claim 249, wherein the fumarateis dimethyl fumarate.
 251. The method of claim 244, wherein theadministering is of 240 mg twice daily of dimethyl fumarate.
 252. Themethod of claim 244, wherein the administering is of 120 mg dimethylfumarate twice daily for 7 days, followed by 240 mg dimethyl fumaratetwice daily as a maintenance dose.
 253. The method of claim 244, whereinthe administering is of not greater than 720 mg daily total fumarates.254. The method of claim 244, wherein the administering is of notgreater than 480 mg daily total fumarates.
 255. The method of any ofclaims 245 and 250-254, wherein the pharmaceutical composition consistsessentially of dimethyl fumarate.
 256. The method of any of claims251-255, wherein the pharmaceutical composition is in the form of atablet or a capsule.
 257. The method of any of claims 251-255, whereinthe pharmaceutical composition is in the form of an enterically coatedtablet.
 258. The method of any of claims 251-255, wherein thepharmaceutical composition is in the form of a capsule containingenterically coated microtablets.
 259. The method of any of claims233-258, wherein the multiple sclerosis is a relapsing form of multiplesclerosis.
 260. A method of treating a patient with multiple sclerosiscomprising: (a) prior to initiating treatment of the patient with apharmaceutical composition comprising a fumarate: (i) performing acomplete blood count including lymphocyte count; and (ii) if thelymphocyte count is found to be below the normal range, consideringalternative causes of lymphopenia, and taking corrective measures asappropriate regarding said alternative causes; and (b) administeringsaid pharmaceutical composition to the patient, wherein the fumarate isa dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkylfumarate and a monoalkyl fumarate, a prodrug of monoalkyl fumarate, adeuterated form of any of the foregoing, or a pharmaceuticallyacceptable salt, clathrate, solvate, tautomer, or stereoisomer of any ofthe foregoing, or a combination of any of the foregoing; with theproviso that ethyl hydrogen fumarate calcium salt, ethyl hydrogenfumarate magnesium salt, ethyl hydrogen fumarate zinc salt, and ethylhydrogen fumarate copper salt are not present in the pharmaceuticalcomposition.
 261. A method of treating a patient with multiple sclerosiscomprising: (a) repeatedly administering a pharmaceutical compositioncomprising a fumarate to the patient; wherein the fumarate is a dialkylfumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate anda monoalkyl fumarate, a prodrug of monoalkyl fumarate, a deuterated formof any of the foregoing, or a pharmaceutically acceptable salt,clathrate, solvate, tautomer, or stereoisomer of any of the foregoing,or a combination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition; and (b)obtaining a complete blood count including lymphocyte count every 3months after starting therapy of said patient with said pharmaceuticalcomposition.
 262. The method of claim 261, which further comprisesdiscontinuing administering of said pharmaceutical composition to saidpatient when the patient has a lymphocyte count less than 0.7×10⁹/L thatis confirmed on repeat testing after 3 months.
 263. A method of treatinga patient with multiple sclerosis comprising (a) administering apharmaceutical composition comprising a fumarate to the patient; whereinthe fumarate is a dialkyl fumarate, a monoalkyl fumarate, a combinationof a dialkyl fumarate and a monoalkyl fumarate, a prodrug of monoalkylfumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that ethyl hydrogen fumarate calcium salt,ethyl hydrogen fumarate magnesium salt, ethyl hydrogen fumarate zincsalt, and ethyl hydrogen fumarate copper salt are not present in thepharmaceutical composition; and (b) monitoring the patient closely forsigns or symptoms of appearance of new neurological dysfunction if thepatient experiences lymphopenia after administering of saidpharmaceutical composition.
 264. A method of improving safety intreatment of a patient with multiple sclerosis comprising monitoring apatient with multiple sclerosis who is being treated with apharmaceutical composition comprising a fumarate, and who experienceslymphopenia, for signs or symptoms of appearance of new neurologicaldysfunction; wherein the fumarate is a dialkyl fumarate, a monoalkylfumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate,a prodrug of monoalkyl fumarate, a deuterated form of any of theforegoing, or a pharmaceutically acceptable salt, clathrate, solvate,tautomer, or stereoisomer of any of the foregoing, or a combination ofany of the foregoing; with the proviso that ethyl hydrogen fumaratecalcium salt, ethyl hydrogen fumarate magnesium salt, ethyl hydrogenfumarate zinc salt, and ethyl hydrogen fumarate copper salt are notpresent in the pharmaceutical composition.
 265. The method of claim 263or 264 wherein the signs or symptoms comprise motor dysfunction andcognitive or psychiatric symptoms.
 266. The method of any one of claims263-265 which further comprises: if PML is suspected, withholdingtreatment with said pharmaceutical composition immediately andperforming further evaluations.
 267. A method of treating multiplesclerosis in a patient who is being treated with a multiple sclerosisdisease-modifying therapy other than a pharmaceutical compositioncomprising a fumarate; wherein the fumarate is a dialkyl fumarate, amonoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkylfumarate, a prodrug of monoalkyl fumarate, a deuterated form of any ofthe foregoing, or a pharmaceutically acceptable salt, clathrate,solvate, tautomer, or stereoisomer of any of the foregoing, or acombination of any of the foregoing; with the proviso that ethylhydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt,ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate coppersalt are not present in the pharmaceutical composition; said methodcomprising the following steps in the stated order: (a) stoppingadministration of said multiple sclerosis disease-modifying therapy tosaid patient; (b) considering the half-life and mode of action of saidmultiple sclerosis disease-modifying therapy in order to avoid anadditive immune effect whilst at the same time minimizing the risk ofdisease reactivation; and (c) administering the pharmaceuticalcomposition comprising the fumarate to the patient.
 268. A method oftreating multiple sclerosis in a patient who is being treated withinterferon or glatiramer acetate, said method comprising: (a)discontinuing administration of interferon or glatiramer acetate to thepatient; and (b) immediately after said discontinuing, startingadministering to the patient of a pharmaceutical composition comprisinga fumarate; wherein the fumarate is a dialkyl fumarate, a monoalkylfumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate,a prodrug of monoalkyl fumarate, a deuterated form of any of theforegoing, or a pharmaceutically acceptable salt, clathrate, solvate,tautomer, or stereoisomer of any of the foregoing, or a combination ofany of the foregoing; with the proviso that ethyl hydrogen fumaratecalcium salt, ethyl hydrogen fumarate magnesium salt, ethyl hydrogenfumarate zinc salt, and ethyl hydrogen fumarate copper salt are notpresent in the pharmaceutical composition.
 269. The method of claim 267or 268, wherein the method further comprises performing an MRI on thepatient before said starting administering to the patient of thepharmaceutical composition comprising the fumarate.
 270. A method oftreating a patient with multiple sclerosis comprising: (a) administeringa pharmaceutical composition comprising a fumarate to the patient;wherein the fumarate is a dialkyl fumarate, a monoalkyl fumarate, acombination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug ofmonoalkyl fumarate, a deuterated form of any of the foregoing, or apharmaceutically acceptable salt, clathrate, solvate, tautomer, orstereoisomer of any of the foregoing, or a combination of any of theforegoing; with the proviso that ethyl hydrogen fumarate calcium salt,ethyl hydrogen fumarate magnesium salt, ethyl hydrogen fumarate zincsalt, and ethyl hydrogen fumarate copper salt are not present in thepharmaceutical composition; and (b) prior to the initial administeringof the pharmaceutical composition comprising the fumarate to thepatient, and periodically during treatment of said patient with saidpharmaceutical composition comprising the fumarate, having a blood testdone to count the number of white blood cells in the patient; and (c)considering stopping said treatment with said pharmaceutical compositioncomprising the fumarate if the number of white blood cells decreasesduring said treatment.
 271. The method of any of claim 260, 261, 263,267, 268, or 270, wherein the administering of said pharmaceuticalcomposition is done orally.
 272. The method of any of claims 260-272,wherein the pharmaceutical composition comprises a therapeuticallyeffective amount of the fumarate and a pharmaceutically acceptablecarrier.
 273. The method of claim 272, wherein the pharmaceuticalcomposition is in the form of a tablet or a capsule.
 274. The method ofclaim 272, wherein the pharmaceutical composition is in the form of anenterically coated tablet.
 275. The method of claim 272, wherein thepharmaceutical composition is in the form of a capsule containingenterically coated microtablets.
 276. The method of any of claims260-275, wherein the fumarate is dimethyl fumarate and/or monomethylfumarate.
 277. The method of claim 276, wherein the fumarate is dimethylfumarate.
 278. The method of claim 271, wherein the administering is of240 mg twice daily of dimethyl fumarate.
 279. The method of claim 271,wherein the administering is of 120 mg dimethyl fumarate twice daily for7 days, followed by 240 mg dimethyl fumarate twice daily as amaintenance dose.
 280. The method of claim 271, wherein theadministering is of not greater than 720 mg daily total fumarates. 281.The method of claim 271, wherein the administering is of not greaterthan 480 mg daily total fumarates.
 282. The method of any of claims 272and 277-281, wherein the pharmaceutical composition consists essentiallyof dimethyl fumarate.
 283. The method of any of claims 278-282, whereinthe pharmaceutical composition is in the form of a tablet or a capsule.284. The method of any of claims 278-282, wherein the pharmaceuticalcomposition is in the form of an enterically coated tablet.
 285. Themethod of any of claims 278-282, wherein the pharmaceutical compositionis in the form of a capsule containing enterically coated microtablets.286. The method of any of claims 260-285, wherein the multiple sclerosisis a relapsing form of multiple sclerosis.
 287. A method of treating apatient with multiple sclerosis comprising: (a) prior to initiatingtreatment of the patient with a pharmaceutical composition consistingessentially of dimethyl fumarate and/or monomethyl fumarate: (i)performing a complete blood count including lymphocyte count; and (ii)if the lymphocyte count is found to be below the normal range,considering alternative causes of lymphopenia, and taking correctivemeasures as appropriate regarding said alternative causes; and (b)administering said pharmaceutical composition to the patient.
 288. Amethod of treating a patient with multiple sclerosis comprising: (a)repeatedly administering a pharmaceutical composition consistingessentially of dimethyl fumarate and/or monomethyl fumarate to thepatient; and (b) obtaining a complete blood count including lymphocytecount every 3 months after starting therapy of said patient with saidpharmaceutical composition.
 289. The method of claim 288, which furthercomprises discontinuing administering of said pharmaceutical compositionto said patient when the patient has a lymphocyte count less than0.7×10⁹/L that is confirmed on repeat testing after 3 months.
 290. Amethod of treating a patient with multiple sclerosis comprising (a)administering a pharmaceutical composition consisting essentially ofdimethyl fumarate and/or monomethyl fumarate to the patient; and (b)monitoring the patient closely for signs or symptoms of appearance ofnew neurological dysfunction if the patient experiences lymphopeniaafter administering of said pharmaceutical composition.
 291. A method ofimproving safety in treatment of a patient with multiple sclerosiscomprising monitoring a patient with multiple sclerosis who is beingtreated with a pharmaceutical composition consisting essentially ofdimethyl fumarate and/or monomethyl fumarate, and who experienceslymphopenia, for signs or symptoms of appearance of new neurologicaldysfunction.
 292. The method of claim 290 or 291 wherein the signs orsymptoms comprise motor dysfunction and cognitive or psychiatricsymptoms.
 293. The method of any one of claims 290-292 which furthercomprises: if PML is suspected, withholding treatment with saidpharmaceutical composition immediately and performing furtherevaluations.
 294. A method of treating multiple sclerosis in a patientwho is being treated with a multiple sclerosis disease-modifying therapyother than a pharmaceutical composition consisting essentially ofdimethyl fumarate and/or monomethyl fumarate; said method comprising thefollowing steps in the stated order: (a) stopping administration of saidmultiple sclerosis disease-modifying therapy to said patient; (b)considering the half-life and mode of action of said multiple sclerosisdisease-modifying therapy in order to avoid an additive immune effectwhilst at the same time minimizing the risk of disease reactivation; and(c) administering the pharmaceutical composition consisting essentiallyof dimethyl fumarate and/or monomethyl fumarate.
 295. A method oftreating multiple sclerosis in a patient who is being treated withinterferon or glatiramer acetate, said method comprising: (a)discontinuing administration of interferon or glatiramer acetate to thepatient; and (b) immediately after said discontinuing, startingadministering a pharmaceutical composition consisting essentially ofdimethyl fumarate and/or monomethyl fumarate to the patient.
 296. Themethod of claim 294 or 295, wherein the method further comprisesperforming an Mill on the patient before said starting administering tothe patient of said pharmaceutical composition consisting essentially ofdimethyl fumarate and/or monomethyl fumarate.
 297. A method of treatinga patient with multiple sclerosis comprising: (a) administering apharmaceutical composition consisting essentially of dimethyl fumarateand/or monomethyl fumarate to the patient; and (b) prior to the initialadministering of said pharmaceutical composition to the patient, andperiodically during treatment of said patient with said pharmaceuticalcomposition, having a blood test done to count the number of white bloodcells in the patient; and (c) considering stopping said treatment withsaid pharmaceutical composition if the number of white blood cellsdecreases during said treatment.
 298. The method of any of claim 287,288, 290, 294, 295, or 297, wherein the administering is done orally.299. The method of any of claims 287-298, wherein the pharmaceuticalcomposition comprises a therapeutically effective amount of the fumarateand a pharmaceutically acceptable carrier.
 300. The method of claim 299,wherein the pharmaceutical composition is in the form of a tablet or acapsule.
 301. The method of claim 299, wherein the pharmaceuticalcomposition is in the form of an enterically coated tablet.
 302. Themethod of claim 299, wherein the pharmaceutical composition is in theform of a capsule containing enterically coated microtablets.
 303. Themethod of any of claims 287-302, wherein the fumarate is dimethylfumarate and/or monomethyl fumarate.
 304. The method of claim 303,wherein the fumarate is dimethyl fumarate.
 305. The method of claim 298,wherein the administering is of 240 mg twice daily of dimethyl fumarate.306. The method of claim 298, wherein the administering is of 120 mgdimethyl fumarate twice daily for 7 days, followed by 240 mg dimethylfumarate twice daily as a maintenance dose.
 307. The method of claim298, wherein the administering is of not greater than 720 mg daily totalfumarates.
 308. The method of claim 298, wherein the administering is ofnot greater than 480 mg daily total fumarates.
 309. The method of any ofclaims 299 and 304-308, wherein the pharmaceutical composition consistsessentially of dimethyl fumarate.
 310. The method of any of claims305-309, wherein the pharmaceutical composition is in the form of atablet or a capsule.
 311. The method of any of claims 305-309, whereinthe pharmaceutical composition is in the form of an enterically coatedtablet.
 312. The method of any of claims 305-309, wherein thepharmaceutical composition is in the form of a capsule containingenterically coated microtablets.
 313. The method of any of claims287-312, wherein the multiple sclerosis is a relapsing form of multiplesclerosis.